Since shock is a syndrome caused by inadequate tissue perfusion, the final common pathway for the pathophysiological changes is the microcirculation. In the early stages of septic shock there is vasodilatation, maldistribution of flow, arteriovenous shunting and increased capillary permeability with interstitial oedema. Although these microvascular abnormalities may largely account for the reduced oxygen extraction often seen in septic shock there may also be a primary defect of cellular oxygen utilization. Initially, before hypovolaemia supervenes, or when therapeutic replacement of circulating volume has been adequate, cardiac output is usually high and peripheral resistance low. Vasodilatation and increased capillary permeability also occur in anaphylactic shock.
In the initial stages of other forms of shock, and sometimes when hypovolaemia supervenes in sepsis and anaphylaxis, increased sympathetic activity causes constriction of both precapillary arterioles and, to a lesser extent, the postcapillary venules. This helps to maintain the systemic blood pressure. In addition, the hydrostatic pressure within the capillaries falls and fluid is mobilized from the extravascular space into the intravascular compartment. If shock persists, the accumulation of metabolites, such as lactic acid and carbon dioxide, combined with the release of vasoactive substances, causes relaxation of the precapillary sphincters, while the postcapillary venules, which are more sensitive to hypoxic damage, become relatively unresponsive to these substances and remain constricted. Blood is therefore sequestered within the dilated capillary bed and fluid is forced into the extravascular spaces, causing interstitial oedema, haemoconcentration, and an increase in viscosity.
This reduction in flow through the microcirculation, combined with the increase in viscosity, makes the blood highly coagulable. There is also systemic activation of the clotting cascade and platelet aggregation with clot formation occurring within the capillary bed. Plasminogen is converted to plasmin, which breaks down these clots, liberating fibrin/fibrinogen degradation products (FDPs). The cells that are supplied by capillaries blocked by this process of disseminated intravascular coagulation (DIe) (see p. 345) inevitably become hypoxic and eventually die. Tissue ischaemia is further exacerbated as capillaries are compressed by interstitial oedema. In this way vital organs may suffer serious damage. Finally, because clotting factors and platelets are consumed in DIe, they are unavaila le for haemostasis elsewhere and a coagulation defect results-hence the alternative name for DIe of consumption coagulopathy’. This process occurs earlier and is more severe in septic shock. The capillary endothelium can be damaged by a number of factors (particularly in septic shock), including DIe, micro emboli, release of vasoactive compounds, complement, and activated leucocytes. Capillary permeability is thereby increased and fluid is lost into the extravascular space, causing further hypovolaemia, interstitial oedema and organ dysfunction.
Gluconeogenesis and triglyceride formation are stimulated by increased glucagon and catecholamine levels, whilst glucagon increases hepatic mobilization of glucose from glycogen. Catecholamines inhibit insulin release and reduce peripheral glucose uptake. Combined with elevated circulating levels of other insulin antagonists such as cortisol and GH these changes ensure that the majority of shocked patients are hyperglycaemic. Occasionally hypoglycaemia is precipitated by depletion of hepatic glycogen stores and inhibition of gluconeogenesis. Muscle proteolysis is initiated to provide energy and hepatic protein synthesis is preferentially augmented to produce the ‘acute phase reactants’.
Once the supply of oxygen to the cells is insufficient for continuation of the tricarboxylic acid (TeA) cycle, production of energy in the form of ATP becomes dependent on anaerobic metabolism. Under these circumstances, glucose is metabolized in the normal way to pyruvate but is then converted to lactate instead of entering the Krebs cycle. The H+ ions released cause a metabolic acidosis. This pathway is relatively inefficient in terms of energy production. Eventually, because of the reduced availability of ATP, the sodium pump fails, cells swell due to accumulation of salt and water, and potassium losses increase. In the final stages, release of lysosomal enzymes may contribute to cell death.
Multiple organ failure (MOF)
Impaired tissue perfusion, microcirculatory abnormalities, and defective oxygen utilization precipitated by dissemination of the inflammatory response with the systemic release of ‘mediators’ (see above) can damage vital organs. The most severely ill patients may develop MOF, which is almost invariably associated with persistent or recurrent sepsis. Following severe shock, damage to the mucosa of the gastrointestinal tract may allow bacteria or endotoxin Within the gut lumen to gain access to the circulation, thereby perpetuating the generalized inflammatory response. Sequential failure of organs occurs progress ively over weeks, although the pattern of organ dysfunction is variable. In most cases the lung is the first organ to be affected with the development of the adult respiratory distress syndrome (ARDS) (see below) in association with cardiovascular instability and deteriorating renal function. Secondary pulmonary infection is common in ARDS, acting as a further stimulus to the inflammatory response. Later, liver and renal failure develop. Characteristically, these patients initially have a hyperdynamic circulation with vasodilatation and a high cardiac output. Eventually, however, cardiovascular collapse supervenes and is the usual terminal event.
Treatment is supportive and prevention of organ damage in those at risk is therefore crucial. Aggressive resuscitation is essential and activation of macrophages must be prevented or minimized by early excision of devitalized tissue and drainage of infection. Preservation of the integrity of the gut mucosal barrier is also necessary by aggressive haemodynamic support in order to maximize splanchnic perfusion. Early enteral feeding may also be beneficial. Early recognition of organ dysfunction and prompt intervention may reverse organ impairment and improve outcome.
The mortality of MOF is extremely high; factors affecting outcome include the number of organs that fail and the duration of organ failure.