Two major consensuses have defined sepsis. The first, in Toronto 1993, introduced the idea of Systemic Inflammatory Response Syndrome, an inflammatory state affecting the whole body usually an immune response to infection but not necessarily so3. SIRS is recognised as the presence of two or more criteria listen in Appendix-Table1. Thus sepsis can be defined as SIRS that is induced by infection. Severe sepsis is when there is dysfunction of at least one organ/organ system is present. In 2001 the International Sepsis Definition Conference modified this model of SIRS introducing the concept of staging based on four separate characteristics designated the acronym PIRO, predisposition, infection, response and organ dysfunction respectively3.
Our immune system is well versed in fighting harmful pathogens though innate and adaptive immunity. Innate immunity is our first life of defence which includes physical barriers as well as cells such as neutrophils and macrophages. The complex adaptive immunity is much more specific and is able to provide personalised attack against pathogens.
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Innate immune system and humoral components are activated in early sepsis. The outer cell products (lipopolysaccharide or lipoteichoic acid) of G- and G+ bacteria binding to toll-like receptors (TLR) is the speculated to be the most significant cause of bacterial sepsis4,8. Intermediary binding molecules such as CD14 facilitate this binding. These TLR are found in leukocytes and macrophages, their activation results in liberation of pro-inflammatory cytokines, reactive oxygen species, nitric oxide (NO), proteases and pore-forming molecules which all bring about bacterial killing4. These molecules are also capable of damaging the host for example nitric oxide (NO) causes reduced sensitivity to circulating catecholamines, sepsis-induced mitochondrial dysfunction and reduced systemic vascular resistance as a result of vasodilation4,15.
Aberrant inflammatory mediator production has long been speculated to be a mediator of sepsis. The hyperinflammatory hypothesis links sepsis directly to the exuberant production of proinflammatory molecules such a TNF, IL-1 and IL-63. These mediators lead to production of mediators downstream such as prostaglandins and phospholipase A2 which have the capabilities to increase capillary permeability. TNF also plays a role in recruiting immune cells to inflammatory sites through adhesion molecules and chemokines36. Evidence for this hypothesis comes from studies that have found sepsis patients with increased levels of TNF are at an increased risk of death, however trials aimed at blocking TNF did not yield favourable response3, perhaps suggesting that the mechanism is far more complex. Another theory suggested that immunosuppression rather than immunostimulation could be a mediator of sepsis. This is supported by recent findings which show some sepsis patients with reduced production of TNHF and IL-63,5,6. These studies also support the finding that even though TNF was reduced IL-10 production was not impaired3,5,6. Thus they concur that pro-inflammatory response could not be initiated while anti-inflammatory response continued unabated. However clinical trials with immunostimulation have yet to be effective.
Alterations in coagulation system though inflammatory cytokines IL-1 and TNF-Î± activate the extrinsic pathway of coagulation and lead to thrombin production, which go on to produce fibrin clots in microvasculature8. The mediators also lead to the production of plasminogen activator inhibitor-1 which is a potent inhibitor of fibrinolysis further accelerating this process15. Bodyâ€™s naturally occurring modulators of inflammation such as activated protein C (APC) are also downregulated. APC turns off thrombin production and also restores fibrinolytic potential by inhibiting plasminogen activator inhibitor-1. Success of APC in clinical trials demonstrates clear alterations in coagulation systems, its success could also be due to APCâ€™s anti-inflammatory properties, including inhibition of proinflammatory cytokines9-11.
Cellular functions can become dysfunctional in sepsis. Significant of these is apoptosis and necrosis. Apoptosis can contribute to pathogenesis by delayed removal of cells that should be removed such as neutrophils and early removal of useful cells such as lymphocytes. Studies have found septic patients having significantly more apoptosis of lymphocytes7,this can be the cause of sepsis especially in patients that have a failure to produce cytokines as discussed above. Although neutrophils play an important role in clearing infection their delayed apoptosis can cause them to persist longer in blood which has the potential to cause organ injury3.
Sepsis can leads to organ failure and death through a cascade of hyperinflammatory reactions and abnormal coagulation. The cardiovascular system in general can be hugely affected by sepsis. Shunting of blood though collateral vessels, physical obstruction from microthrombi, and increased blood viscosity all lead to disorder of blood flow4. This means the capillaries in patients with sepsis have poor flow, reduced perfusion and capillary oedema meaning oxygen has a larger diffusion area to cross4. This explains why organs may become hypoxic even though blood flow to the organ may increase15. ATP production can also be impaired by NO (produced as a result of cytokines release) which combines with oxygen free radicals (O2-) producing peroxynitrite (ONOO-). All three compounds can bind to proteins in electron transport chain impairing ATP production4. This falling intra-cellular ATP concentration can perhaps explain the eventual symptoms such as anuria and hypotension4.
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The resulting hypovalemia combined with reduced left ventricular contractility lead to hypotension. The body compensates initially by increasing heart rate to increase cardiac output but this mechanism becomes exhausted leading to hypoperfusion and shock15. Despite hypotension myocardial perfusion and myocardial use of oxygen in preserved in septic shock suggesting that heart dysfunction is not related to perfusion4. Therefore the decompensation seen in late sepsis could be as a result of myocardial depression and failure to maintain elevated filling pressures4.
In early sepsis endothelial leakage, infiltration of neutrophils, loss of surfactant contributes to respiratory dysfunction16. In late sepsis inflammatory pulmonary oedema may develop which can go on to manifest clinically as acute respiratory distress syndrome (ARDS)4. Normally NO plays a role in distribution of blood between renal cortex and medulla. Through its direct and indirect effects on mitochondrial energy production it can affect tubular function, which is highly energy dependant4. The kidneys may particularly be vulnerable to cytokine-induced and oxidative injuries16. The activation of coagulation pathway and subsequent fibrin deposition may also induce renal injury16. Sepsis is also show to affect the brain. The post-mortem brains of septic patients various cerebral lesions, ischaemic haemorrhages and microthrombi although this could be as a result of the drying process or sampling abnormalities the presentation of septic patients with encephalopathy may indicate otherwise16. What is clear is that the consequences of sepsis are extensive affecting homeostasis though cellular and organ dysfunction.
Treatment of Sepsis
The first step in the emergency treatment of sepsis will be to obtain a full history, then access ABCDE where they signify Airway, Breathing, Circulation, Disability, and Exposure respectively35. Supplementary oxygen and mechanical ventilation are available should the patient need support. Several tests can be performed in the emergency department including lactate measurements, full blood count, clotting factors and liver function tests. These give an idea of the current state of the patient. Before giving patients intravenous broad-spectrum antibiotics it is advised to take blood cultures from two different sites 35,17,18. The administration of broad-spectrum antibiotics should be given within 1 hour of diagnosing acute sepsis, as for every hour delay in administration there is a 6% rise in mortality17,19. The intravenous administration will usually be given for around 7-10 days. Once a specific bacterium has been identified through cultures a selective antibody can be given. Although sepsis can be caused by virus, broad spectrum antibiotic treatment will still be started as it is too dangerous to delay treatment until an accurate diagnosis is made18.
Source control treatments are physical measures undertaken to eliminate the source of infection36. This would involve eradicating the source of the infection such as an abscess or infected wound and in serious cases surgical removal of tissue maybe required. Evidence of recent studies proposes the idea that there is little reason to delay source control for more than a few hours to allow optimisation and correction of metabolic derangement.
This patient has profound metabolic acidosis with partial respiratory compensation. The metabolic acidosis could be as a result of poor perfusion/hypotension; when the cells are not receiving enough oxygen they will start to respire anaerobically which will result in a build-up of lactic acid; this can be leading to metabolic acidosis. The best way to treat the metabolic acidosis would be to treat the underlying cause by administering inotropic medicines (to increase the force of myocardial contractility) and vasopressors to increase blood volume. Vasopressors are normally used to treat low blood pressure and they act by increasing the reabsorption of water. Dobutamine and Noradrenaline are two of the recommended vasopressors for sepsis. IV fluids are another way to increase blood pressure by increasing the total blood volume18.
Another goal of the treatment would be to maintain adequate organ system function and interrupt any multi-organ dysfunction20. The major focus will be on supporting the cardiac and respiratory system. Therefore, following initial history one would assess airway breathing and administer supplementary oxygen. Although this patient does not have significant hypoxaemia the accelerated oxygen demand can cause acidosis to get worse. The oliguria would prompt one to administer colloid fluids. If the fluids fail to reverse the hypotension and oliguria then vasopressors can be used. Given the fact that the patient is in hospital it would be best to perhaps choose a broad-spectrum antibiotic that can eradicate MRSA or Beta-lactemase resistance bacteria. If the patient continues to shows signs of severe sepsis administering low dose hydrocortisone may help as it has shown in recent research to be effective21,22,23.
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Standardising Sepsis Treatment
The Surviving Sepsis Campaign (SSC) introduced in 2002 is collaboration of professional organisations to standardise the treatment of sepsis and reduce its mortality24. The guidelines highlight the importance of early aggressive management of sepsis before the patient ends up in intensive care unit. SSC bundle form the core of evidence based recommendation and are divided into resuscitation bundles and management bundles. Resuscitation bundle outlines objectives to be completed before 3 hours and 6 hours following presentation-see table in appendix. Measuring lactate levels, obtaining blood culture before administration of broad spectrum antibiotics and administration of crystalloids for hypotension are all goals for the first 3 hours. Maintaining mean arterial pressure >65mmHg through vasopressors (should fluid resuscitation fail) and maintaining central venous pressure of > 8mmHg are all resuscitation goals. Central venous oxygen saturation (ScvO2) is the oxygen saturation of blood returning from the tissue, in other words it is indicator if tissue perfusion just like lactate levels. Maintaining ScvO2 of above 70% could be another way of standardising the treatment and ensuring adequate oxygen delivery to tissue21. Although lactate clearance and ScvO2 both equally effective, ScvO2 allows for immediate intervention should ScvO2 drop below 70%. Management bundle on the other hand outlines goals to be achieved within 24 hours which includes low-dose corticosteroids, glucose control and ventilator support34.
Early recognition of sepsis is vital to survival of the patient thus early goal-directed therapy (EGDT) is one of the proposed initiatives to further manage the patient21. EGDT emphasises quick antibiotic therapy, fluid management and goal-directed therapy for patients that remain hypotensive or severely ill.
Potential Sources of Infection
Infection in almost any part of the body can lead to sepsis. The most common sites of infection leading to sepsis are lungs, urinary tracts abdomen and pelvis25.
Puerperal infection is a generalised term used to describe an infection of the genito-urinary system that is often related to labour, delivery or miscarriage28. These include infections in uterus, urinary tract or any incidental infections such as respiratory tract infections. After miscarriage and childbirth the genital tract has a large bare surface and this can become infected. These infections are usually limited to her cavity and the wall of her uterus however if the infection spreads it will lead to peritonitis and septicaemia27. Bacterial Vaginosis is an example of such a disease where the balance of bacteria within the vagina becomes disrupted; this has been linked to miscarriages in very small number of cases30. Sexually transmitted infections are another potential cause of sepsis. Urinary tract infections from gram-negative beta-lactamase producing organism are other perpetrators in causing sepsis and maternal deaths32.
Following the recent miscarriage tissue that is left behind, known as incomplete miscarriage, could become infected leading to sepsis26. Incomplete miscarriages are managed by minor surgery to remove any foetal tissue and the surgical procedure could also have introduced pathogens which could lead to infection and consequently sepsis. Although the presence of harmful bacteria in the uterus may be enough to cause septic miscarriage long standing research has suggested that the retention of septic products inside the uterus following incomplete miscarriage and stasis of uterine wall can also lead to sepsis29.
This patient could also be prone to extra-genital causes of infection. This includes opportunistic infections such as malaria and respiratory tract infections33. Skin and soft-tissue infections can also be introduced through IV cannulae or injection sites.
In conclusion sepsis is one of the leading causes of death in the UK. It is characterised by derangements such as abnormal coagulation, endothelial injury, excessive TNF, cellular dysfunction. This homeostatic instability along with organ dysfunction is detrimental to oneâ€™s health. Discussion of the pathophysiology of sepsis only highlighted the complex nature of this disease thus emphasising that we have still have a lot to learn. Although several tools are available in the emergency department for treatment, to date the SSC have developed the most comprehensive protocol that can ensure mortality is kept low.