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Pathophysiology of septic shock 

Pathophysiology of septic shock
Pathophysiology of septic shock
Oxford Textbook of Critical Care (2 ed.)

John M. Litell

and Nathan I. Shapiro


Key points

  • Sepsis results from a dysregulated homeostatic response to infection.

  • Immune activation and immunosuppression are both present in sepsis syndromes.

  • The host’s inflammatory and coagulation systems are closely interrelated, and disruptions in both are central to sepsis pathophysiology.

  • Abnormalities in macrovascular, microvascular, endothelial, and mitochondrial function all contribute to the haemodynamic changes and organ failures seen in septic patients.

  • Sepsis mortality increases with successive organ failures.


Sepsis is the result of a complex and dysregulated homeostatic response to infection. Untreated, sepsis progresses to hypoperfusion, hypoxia, and dysfunction at the level of cells, tissues, and organ systems, leading to death in at least 30% of cases [1]‌. The clinical syndrome of sepsis is a manifestation of pro- and anti-inflammatory intermediates and is intimately linked to disruptions in coagulation, microcirculatory flow, and mitochondrial function, leading to common pathways of failure in multiple organ systems. The severity of the response depends on both host and pathogen characteristics and the relevant underlying pathophysiology arises principally from interactions between an infectious agent and the host’s innate immune system.

Innate immunity is characterized by a rapid response capability to novel insults, which results from an interaction between conserved molecular signals on pathogens and corresponding pattern recognition receptors on host immune cells. All non-vertebrate organisms—pathogenic, non-pathogenic, or commensal—express microbial-associated molecular patterns (MAMPs) [2]‌. These bind to pattern recognition receptors (PRR) expressed by host immune cells. The best-known human PRR are the ubiquitous toll-like receptors (TLR), a highly diversified family of cell surface and cytoplasmic receptors for an extraordinary number of microbial invaders and endogenous danger signals.

TLR activation, via multiple secondary signalling pathways, leads to translocation of nuclear factor kappa B (NF-κ‎B), a central regulatory factor for several inflammatory target genes, including pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α‎) and interleukin 1 (IL-1). These trigger the cardinal pathophysiological manifestations of sepsis—leukocyte activation and transmigration, endothelial damage and dysfunction, and increased capillary permeability—resulting in hypovolaemia and exposure of tissue factor to circulating coagulation factors [3]‌.

Circulating apoptotic or necrotic cell debris can initiate a similar response via damage-associated molecular pattern (DAMP) receptors. Since ischaemia and necrosis often accompany infection, these responses can coexist in positive feedback loops, wherein PRR are stimulated both by infectious agents and by damaged host cells resulting from the infection.

The pro-inflammatory cytokine high-mobility group box 1 protein (HMGB1) is also thought to play an important role late in the pathogenesis of sepsis. Several hours after exposure to infectious stimuli, macrophages, dendritic cells, and natural killer cells all release HMGB1, as do necrotic host cells. Apoptotic host cells may trigger release of HMGB1 from macrophages. The receptor for advanced glycation end-products (RAGE) may also contribute to pro-inflammatory signalling in sepsis. HMGB1 protein and several other endogenous ligands are recognized by RAGE, which may then activate NF-κ‎B signalling pathways.

Historically, sepsis was thought to result from disproportionate release of pro-inflammatory mediators in response to infection. More recent work has identified features of both hyperinflammation and immunosuppression in sepsis [4]‌. That both are relevant is fairly clear, but the timing and relative contributions of their effects are uncertain.

Immune suppression in sepsis is partially due to elaboration of anti-inflammatory cytokines and likely also to lymphocyte apoptosis. TLR activation results in upregulation of signal transduction pathways, which lead to DNAse activation and apoptosis. Interestingly, although necropsy studies in septic patients reveal relatively little parenchymal cell death in failing organs, they do show profound apoptotic loss of components of cellular immunity. In addition to responding to anti-inflammatory cytokines, immune cells are also receptive to efferent vagal suppression via cholinergic receptors.

Inflammation and coagulation

There is substantial cross-talk between the inflammatory and coagulation systems, the full extent of which is still not elucidated. These systems are evolutionarily linked. Although they have diverged in humans and other vertebrates, in invertebrate species, inflammation and coagulation are performed by a single cell type, the haemocyte, reflecting an evolutionary precursor [5]‌.

The coagulant response to an infectious insult is initiated by increased amounts of circulating tissue factor, which results from endothelial permeability as well as haematogenous spread of necrotic debris. This initiates a procoagulant response resulting in thrombin generation and increased fibrin formation, balanced by early fibrinolysis via increased expression of plasminogen activator. Further counterbalance is provided by increased expression of plasminogen activator inhibitor.

These effects can proceed rapidly, and coagulation is an essential protective response to infection [6]‌. The formation of fibrin nets traps not only activated platelets, but also bacteria and leukocytes. By aggregating bacteria in a region of decreasing nutrient supply, bacterial trapping limits both haematogenous spread and local growth. The majority of known human bacterial pathogens employ fibrinolytic properties to evade these fibrin nets.

When overwhelmed, the pro- and anticoagulant responses to infection can accelerate to a consumptive coagulopathy and disseminated intravascular coagulation (DIC). Widespread microvascular thrombosis contributes to multi-organ failure, resulting in a progressive cycle of maladaptive immune response, dysregulated coagulation, and deepening critical illness.

Microcirculatory effects

Organ perfusion is impaired not only by abnormalities in macrovascular flow (oxygen circulation), but also by direct effects on the microcirculation (oxygen distribution) and the mitochondria (oxygen processing). A complex interplay between the endothelium, vascular smooth muscle, and the cellular components of blood is largely responsible for capillary blood flow, nutrient delivery, exchange of products of cellular respiration, and coagulation and immune function. The autoregulatory capability of the microcirculation, as well as arterial driving pressure and the physical characteristics of the blood, can all be adversely impacted in sepsis [7]‌.

Toxic products of infection, pro-inflammatory mediators, reactive oxygen species (ROS), activated host leukocytes, and inducible nitric oxide synthase all exert direct effects on vascular tone, integrity, and endothelial cell signalling, leading to increased venous capacitance and massive capillary leak. Clinically, these contribute to impaired cardiac filling pressures that can be partially restored by volume resuscitation.

However, conventional measures of fluid balance and effective circulating volume do not fully reflect the substantial extravasation of fluids due to endothelial dysfunction, which can persist beyond initial resuscitation. Loss of normal autoregulatory function in end-organ tissue beds also contributes to maldistribution of blood flow, with hyperaemia at some sites and hypoperfusion at others.

Flow limitations are only part of the problem. Mitochondrial oxygen utilization is also disrupted, resulting in a cytopathic hypoxia even in regions with normal or supranormal blood flow [8]‌. Taken together, these changes result in a persistent anaerobic metabolism and lactic acidosis even after the restoration of adequate circulating volume. These microcirculatory and mitochondrial abnormalities are undetected by conventional haemodynamic measurements.

Organ system manifestations

Septic patients often manifest single or multiple organ failures, which share characteristic pathophysiological mechanisms. Mortality in these patients has been shown to roughly double for each additional organ system failure. Recovery of organ failures, where possible, is largely accomplished by reversal of the underlying insult and associated host inflammatory response.


Approximately one-third of critically ill patients experience AKI, with a mortality of 20–60% depending on the severity of the injury. Half of these cases are due to sepsis. For several reasons, the pathophysiology of septic AKI is incompletely understood. Ethical restrictions preclude widespread biopsy collection from critically ill patients, so histopathological data are limited. Most human data are flawed and over 30 years old [9]‌. Animal models created to fill this knowledge gap have largely relied upon mechanisms—such as ischaemia/reperfusion and drug toxicity—that are probably only indirectly relevant. More recent animal and human studies have called into question the theory that septic AKI involves renal hypoperfusion and tubular ischaemia.

Septic shock is typically a hyperdynamic hypotensive state. While septic AKI is typically attributed to renal hypoperfusion, this may not actually be the case. Animal data have revealed that hyperdynamic septic subjects often have increased renal blood flow, as the renal arterioles undergo the same dilation as the systemic vasculature. Septic AKI may therefore be misclassified, due instead to hyperaemic renal failure, with tubular cell injury and dysfunction due primarily to non-haemodynamic factors [10]. These may include the cytokines, coagulation factors, and other inflammatory and neuroendocrine mediators circulating in supranormal concentrations in septic patients.

Renal parenchymal cells express TLR, which may be directly activated by endotoxin. TNF, one of the principal inflammatory cytokines released after TLR activation, is also bound in increased quantities to renal parenchymal receptors in animals with experimentally induced septic AKI [10]. Thus, the dysfunction seen in septic AKI may result from both remote activation and local propagation.

Indirect evidence for this is seen in studies of remote effects of single organ injury, for example the development of AKI in rabbits with acute respiratory distress syndrome who are ventilated with injurious tidal volumes, or the initiation of in vitro apoptosis of renal tubular cells treated with plasma from burn patients [11]. This type of crosstalk between the kidneys and remotely failing organs suggests that our concept of AKI in sepsis as primarily a problem of renal perfusion is relatively rudimentary.

Renal tubular cell apoptosis is likely one of the non-haemodynamic mechanisms underlying septic AKI [12]. In contrast to ischaemic necrosis, apoptosis is triggered by intercellular signals and results in an organized sequence of steps that terminally extinguish cell function. Prevention of this sequence of events requires more than simply restoration of renal perfusion pressure. Identification of the signals responsible for the initiation of renal tubular cell death may allow the prevention of their release or blockade of their interaction with receptors in vulnerable renal tissues.


Given its exposure to both the external environment and the systemic circulation, the lung can be both a primary site of infection or suffer collateral damage during sepsis. The extent and fragility of the pulmonary parenchyma renders it vulnerable to circulating mediators and chemical and mechanical disruption. Multiple direct and indirect inflammatory aetiologies can lead to acute pulmonary parenchymal injury, manifested by impaired alveolocapillary membrane integrity and non-cardiogenic pulmonary oedema.

In the case of acute lung injury as a secondary consequence of remote insults, systemically activated leukocytes traversing the pulmonary microcirculation migrate into the interstitium, where they perpetuate the inflammatory response locally via signalling intermediates. With local infections, TLR activation leads to microbial clearance or, if overwhelmed, necrosis and apoptosis of parenchymal cells. Since these processes result in DAMP release they are in themselves immunogenic [3]‌. This results in amplified local leukocyte activation, endothelial dysfunction, and interstitial oedema, as well as activation of platelets and coagulation factors. Progressive parenchymal dysfunction manifests as pulmonary shunt with refractory hypoxemia, contributing to multi-organ dysfunction.


Sepsis disrupts normal cardiovascular function through overlapping effects on myocardial function, vascular tone, and capillary integrity. Although commonly understood as a subtype of distributive shock, sepsis also involves features of hypovolemic and cardiogenic shock. Systemic presence of inflammatory cytokines contributes to peripheral arterial dilation, diffuse capillary leak, decreased contractility, and reflex tachycardia. Patients generally exhibit diastolic hypotension and decreased mean arterial pressure.

Myocardial dysfunction in sepsis manifests as biventricular dilation, decreased ejection fraction, diastolic dysfunction, and decreased cardiac output [13]. These reversible abnormalities are present even during the hyperdynamic phase of shock. Elevated concentrations of TNF-alpha, IL-2, and IL-6 may exert a direct myocardial depressant effect. Increased nitric oxide generation and dysregulation of intracellular calcium flux are theorized to contribute to cardiomyocyte dysfunction, via unclear mechanisms. Initial biventricular dilation is postulated as a compensatory Frank-Starling response to decreased vascular resistance. However, as with this and other changes in myocardial function during sepsis, it is not clear which are abnormal and which may be protective (e.g. energy-conserving).

Both left and right ventricular function can be impaired in sepsis, the latter being further compromised by increased pulmonary vascular resistance in the case of acute lung injury. To date, most studies of myocardial dysfunction in sepsis have evaluated systolic changes. Diastolic dysfunction also occurs, but it is technically more difficult to assess via echocardiography. As with other organ systems, myocardial dysfunction is likely not simply attributable to ischaemia, illustrated by thermodilution studies demonstrating normal or even supranormal coronary flow. Microcirculatory dysfunction is among the postulated mechanisms.

Structural myocardial structural changes also occur during sepsis, including leukocyte infiltration, interstitial oedema, collagen deposition, and mitochondrial damage, with unclear reversibility and functional consequences. As elsewhere, endothelial dysfunction and TLR activation on circulating leukocytes play central roles, as do locally generated ROS. The resultant interstitial oedema and inflammation are attributed to both leukocyte activation and the direct effects of toxic microbial products, though the degree to which each is responsible for myocardial dysfunction remains unclear. Furthermore, mitochondrial structural and functional abnormalities are seen in human autopsy specimens, though cardiomyocyte apoptosis has thus far primarily been seen in vitro.


As little as one cell layer separates normally sterile tissues from a dense collection of faecal bacteria. Translocation of these microbes or their components is thought to play a role in the initiation or perpetuation of systemic inflammation in critically ill patients. Although the precise mechanisms remain unclear, hypomotility of the gut may contribute to this development [14].

Systemic effects of infection are known to affect gastrointestinal motility, likely due to a combination of effects on the enteric nervous system, sympathetic and vagal input, resident leukocytes, macrophages, and mast cells, and smooth muscle. It is not known whether these occur directly or are mediated by leukocyte signalling, and little is known about the specific associated TLR pathways. The presence of endotoxin and increased production of nitric oxide and prostaglandins are all implicated.

Sepsis-induced ileus likely contributes to a cycle of hypomotility, inflammatory cell recruitment and activation, and production of ROS and inflammatory cytokines. This may compromise the protective intestinal epithelial surface, with subsequent translocation of enteric flora or their PAMPs. The gut contains an unparalleled reservoir of potential pathogens. While some degree of translocation may serve an important immune function, in critically ill patients the homeostatic interplay among normal commensal enteric flora can become dysregulated, and the compromised gut wall may become a potent driver of systemic inflammation and multi-organ dysfunction. Translocation of gut flora and/or PAMPs may explain the delayed appearance of sepsis among some ICU patients, in whom progressive organ dysfunction includes deterioration of the gut mucosal protective barrier. Sepsis-induced ileus may also contribute to micro-aspiration and pulmonary infection, particularly in intubated patients.


Among the neurological manifestations of sepsis, acquired delirium can complicate ICU outcomes and impact recovery. As many as 70% of patients with severe sepsis develop encephalopathy, which is associated with worsened outcomes [15]. Although initially attributed to toxic products of invading microorganisms, septic encephalopathy is now thought to result primarily from the systemic response to infection, including alterations in cerebral haemodynamics and the ratios of amino acid substrates for cerebral metabolism. Other potential causative factors include blood-brain barrier disruption, CNS inflammation, complement activation, increased production of nitric oxide and other vasoactive substances, neurotransmitter dysregulation, and leukocyte recruitment.


An association between sepsis and adrenal insufficiency has been recognized for over a century. As many as 60% of patients with sepsis and septic shock manifest a corticosteroid response that is apparently insufficient, given their severity of illness [16]. Critical illness-related corticosteroid insufficiency (CIRCI), results from decreased production of corticotropin-releasing hormone and its downstream products, as well as diminished sensitivity of peripheral tissues to activated glucocorticoid receptor [17]. The results include an impaired haemodynamic response to sepsis and insufficient downregulation of pro-inflammatory cytokines.

The diagnosis of CIRCI is complicated in part by the lack of an assay for corticosteroid activity at the level of the target tissue. Clinicians must therefore rely on macroscopic features, as well as random measurements of absolute cortisol level and its response to stimulation by exogenous steroid, both of which are less accurate in the setting of sepsis.

The adverse effects of CIRCI seem to be due to its further perturbation of an imbalance between pro-inflammatory mediator overexpression and sepsis-related immune suppression. The optimal steroid replacement strategy must not further worsen this imbalance. Underdosing may allow the inflammatory vasoplegia and microvascular leak to persist, whereas overdosing may increase vulnerability to infectious insults, and can delay wound healing.

Glucose transporter (GLUT) dysfunction, insulin resistance, glucose intolerance, and hyperglycaemia commonly accompany critical illness. In sepsis, hyperglycaemia is likely due to pro-inflammatory cytokine-mediated GLUT dysfunction, sympathetic nervous system activation, and upregulation of counter regulatory hormones and insulin growth factor binding protein. Detrimental cytotoxic effects of hyperglycaemia appear to be mediated by cellular glucose overload and the accumulation of toxic products of glycolysis and oxidative phosphorylation. Multiple investigators have prospectively evaluated the association between glycaemic control and outcomes among critically ill patients, with largely mixed results [18]. For those limited populations in which tight glycaemic control has seemed beneficial, the purported benefits of insulin therapy may be directly due to glycaemic control or to salutary metabolic effects of insulin.


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