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A magic bullet for sepsis – a needle in a haystack or barking up the wrong tree?
BASIC SCIENCE
A magic bullet for sepsis e a needle in a haystack or barking up the wrong tree?
side effects with the potential for further activation of immunological and host responses, leading to additional organ dysfunctions and failures.
Sepsis at a molecular level Microbial triggering (Figure 1) In sepsis, microorganisms release chemicals which interact with the host’s immune system, triggering host T-cell responses which in turn enhance activation of intracellular nuclear transcription factors culminating in a release of numerous inflammatory mediators. Some of the more recognized microbial triggers are described below. Endotoxins are lipopolysaccharides (LPS) released from the cell walls of Gram-negative bacteria. These avidly bind to lipopolysaccharide- binding protein, an acute phase reactant produced by the host, with the resulting complex activating macrophages, T-cells and opsonization processes. Endotoxin has also been detected in cases of Gram-positive sepsis. This may be related to injury to the gut mucosa during severe sepsis of any cause, and translocation of Gram-negative organisms into the systemic circulation. Gram-positive organisms however also release molecules such as peptidoglycans and lipoteichoic acid. These molecules can also activate the host’s immune system via interaction with T-cells. Also some bacteria can release exotoxins (superantigens) that can activate host responses directly without specific mediation by immunological cells (e.g. toxic shock syndrome); exotoxins (proteases and porins) that can directly cause host cell damage; or exotoxins (e.g. tetanus) that directly mediate the disease process. Fungal cell wall material can also stimulate the host’s innate immunity. Anti-endotoxin therapies include non-specific polyclonal antiserums, monoclonal therapies directed against endotoxins, and endotoxin binding proteins. Although some trials have suggested potential benefit with the use of these agents, the biggest downfall in their use is initiating therapy at an early enough phase of confirmed gram negative sepsis to gain benefit.
P adraig Headley Conn Russell
Abstract Severe sepsis causes significant morbidity and mortality and constitutes a considerable burden on the National Health Service. Our understanding of the pathophysiology, molecular processes and genomics is gradually improving. There is increasing attention being paid on trying to find a novel targeted treatment for sepsis. However, no agent to date has weathered clinical trials and analyses. One that came close was activated protein C, but it has now been removed from the market due to lack of clinical efficacy. The purpose of this article is to explore current theories underpinning the scientific basis and pathophysiology of sepsis, and to link it to the search for targeted therapies.
Keywords Critical care; infection; multi-organ failure; pathophysiology; sepsis; systemic inflammatory response
Sepsis/systemic inflammatory response Systemic inflammatory response syndrome (SIRS) encompasses a collection of clinical findings resulting from harmful insults (Box 1). SIRS and sepsis are not synonymous, but rather sepsis is just one common insult resulting in SIRS. Infection is simply the invasion of tissue by microorganisms which then multiply and may or may not have numerous toxic consequences. Sepsis reflects the systemic consequences of infection and is inherently linked to the microbiological activity and its interaction with the host responses. Sepsis is a complex pathological process involving the activation of the innate immune system. As with any immunological process numerous mediators, receptors and chemistry are involved. Genomics is likely to have an impact in these processes, with differing polymorphisms potentially influencing the type and magnitude of effects seen. Dissemination of these responses and their potential dysregulation results in sepsis. Even after the main insult has been eradicated, multi-organ dysfunction can persist. Supportive treatments and interventions used in the management of severe sepsis have a range of
Cytokines: SIRS versus compensatory anti-inflammatory responses (CARS) Once triggered, the host’s immune system will release numerous inflammatory mediators called cytokines. These are polypeptides released by macrophages, T-cells and endothelial cells in response to sepsis and other insults. Tumour necrosis factor (TNF) is one of the first cytokines to be released and is a potent neutrophil activator. Interleukin (IL) -1 is also released and acts synergistically. IL-6 stimulates acute phase reactants and potentates myocardial dysfunction in sepsis. It also is involved in stimulating a fever, cachexia and anaemia. These mediators stimulate many of the features of a systemic inflammatory response. Conversely other anti-inflammatory mediators exist including IL-10 and IL-4. Endogenous inhibitors of the pro-inflammatory mediators are also recognized. The host can also down-regulate inflammatory responses by for example shedding receptors. This is seen with TNF whereby the cell wall receptors are shed and released into circulation as soluble TNF receptors to mop up
draig Headley MB BCH BAO MRCP PgDip(Critical Care) is a Specialty Registrar Pa in Acute Internal Medicine and Intensive Care Medicine at the Ulster Hospital, Belfast, Ireland. Conflicts of interest: none declared. Conn Russell FCA FRCA FICM DIBICM is a Consultant in Anaesthesia and Intensive Care Medicine at the Ulster Hospital, Belfast, Ireland. Conflicts of interest: none declared.
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therefore be the answer. Also with regards studying these mediators during the course of sepsis we cannot even be certain if circulating levels reflect actual local biological activity. This also tempers moves towards directed pharmacological therapies in this area.
Systemic inflammatory response syndrome criteria Temp >38; <36 C Heart rate >90 bpm Respiratory rate >20 bpm Leucocytes >12 or <4 cells/cm3
C C C C
Acute phase reactants An acute phase reactant is a protein, the concentration of which increases or decreases significantly during a systemic insult such as sepsis. It is likely that some proteins decrease in concentration to supply amino acid demand for others (e.g. albumin). A fall in serum albumin is a common sign seen in severe sepsis and serves as a prognostic marker. Some acute phase reactants however are likely to have a physiological role during the insult (e.g. LPS-binding protein binds endotoxins). C-reactive protein is a commonly measured acute phase reactant which acts physiologically to promote opsonization. Of note it is neither specific nor diagnostic of sepsis. An immunoglobulin receptor called sTREM-1 (soluble triggering receptor expressed on myeloid cells-1) can now be measured in the serum, and may prove more specific in identifying infection as a cause for SIRS.3 Other acute phase reactants include serum amyloid A (which is of uncertain importance at present but is linked with secondary amyloidosis in chronic infections); and transferrin (increases of which may help with iron binding and reducing oxidative stresses during insults). The complement pathway is also a complex example of interlinked acute phase reactants with immunological functions. The production of multiple acute phase reactants is likely to contribute to the marked catabolism seen in sepsis, and the development of conditional deficiencies in amino acids such as glutamine due to the cellular requirements to produce some of these proteins in high quantities.
Box 1
and inactivate circulating TNF.1 Processes like this act as a compensatory anti-inflammatory response (CARS).2 Overall this is a very complex and incompletely understood process, which may explain why pharmacological therapies aimed here have yet to show any promise. Certainly there is a process by which, when triggered, the host mounts an inflammatory cascade which is then regulated by antiinflammatory processes to achieve resolution. Harmonizing these conflicting processes to achieve the correct balance intuitively seems crucial for recovery from sepsis. Imbalances due to over- or under-activity of either arm will likely result in poor outcome (Figure 2). It also means that at differing times within the same patient, and to differing extents in different patients, one arm may be more active than the other. Targeting therapy against one mediator across this whole population may not
Microbial triggering Triggering Pathogen-associated molecules Endotoxins Peptidoglycans Fungal cell walls
Exotoxins and superantigens
Prostaglandins4 Prostaglandins and leukotrienes are released from the enzymatic degradation of cell membrane lipids by phospholipases, cyclooxygenases and lipoxygenases during sepsis and contribute to the SIRS/CARS balance. There is potential for these to be further metabolized into numerous other mediators which have numerous effects. The net physiological effect will depend on the nature of the released mix and its overall biologically activity. Examples include prostacyclin which is a potent vasodilator and platelet inhibitor. Conversely thromboxane causes vasoconstriction and platelet aggregation. Platelet-activating factor is another example which causes hypotension, platelet aggregation and vascular permeability. These are many of the features seen in severe sepsis. Prostaglandin and bradykinin inhibitors, alongside non-steroidal anti-inflammatory drugs, have so far failed to show any benefit in the treatment of severe sepsis.
Immune system
Cytotoxic
RESPONSE
Inflammatory responses
Hypothalamusepituitary axis (HPA) Endocrine mediated changes within the host are well recognized in many forms of insult/stress. Sepsis is no different in this respect. While many of these processes are likely to be physiological reactions to help mitigate the extent of the insult, there has been much interest in exploring how some of these processes may in fact be detrimental or could be manipulated in cases of sepsis. The HPA acts as the conductor of the endocrine system and is directly activated in severe sepsis by the systemic release
Gram-negative bacteria – endotoxin
Figure 1
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Systemic inflammatory response syndrome (SIRS) versus compensatory anti-inflammatory responses (CARS) Balancing inflammatory and anti-inflammatory mediators in sepsis Hyper-responsive, persistent inflammation and organ damage, death/recovery
SIRS
Hypo-responsive, nocosomial infection, failure to resolve death/recovery CARS Figure 2
of cytokines, which result in the release of corticotropic-releasing hormone, adenocorticotropic hormone, growth hormone, prolactin and vasopressin; as well as endorphins which are shown to have increasing immunomodulatory as well as analgesic properties. The acute phase response is also relevant here as many of the endogenous hormone-binding proteins change their concentration in severe sepsis. Changes in the systemic binding of hormones will also alter their peripheral biologically activity. These factors make the standard measurement and interpretation of hormone profiles very difficult in these cases. This is evident in the non-thyroidal illness syndrome or sick euthyroid syndrome.5 In this case there appears to be a downregulation of thyroid function on testing, which is of uncertain clinical significance at present. Certainly however these hormonal changes will physiologically regulate cellular metabolics in severe sepsis; and the extent to which they do or do not occur is likely to be significant. The most discussed of the hormonal processes in sepsis is probably the adrenocortical axis. Corticosteroids are well recognized as immune modulators and many of these features seem attractive in the setting of sepsis
(Table 1). In any form of shock, cortisol levels typically rise, with a loss of the natural circadian rhythm. A reduction in cortisol binding globulin also occurs with a rise in free cortisol levels. The extent of the rise in cortisol has been studied in sepsis to see if it is linked to prognosis, with a mixed outcome between the studies. It has been suggested however that patients with high basal cortisol levels, with or without a blunted response to stimulation, have an increased mortality in sepsis.6 Whether this is a cause for increased mortality or simply the effect of being ‘more ill’ is yet to be determined. Also the factors driving these changes, between different patients, are yet to be established. There was previous enthusiasm in the early 1980s for the use of therapeutic dose steroids as immunosuppressants in severe sepsis. This has since been shown to be of no benefit or even detrimental except in predefined clinical conditions.7 Enthusiasm has since moved towards the use of physiological doses of steroids in sepsis. Studies have shown that the use of low dose hydrocortisone in patients who are vasopressor dependent with sepsis have reduced overall vasopressor requirements.8 This however does not translate into a mortality benefit. The endocrine story as with many areas in severe sepsis remains incompletely understood. Studies looking at altering hormonal balance to improve mortality in sepsis face numerous challenges including the cause-effect analogy, patient selection and treatment timing factors, and the difficulties of interpreting routine endocrine tests in this subgroup.
Steroids in sepsis Steroids as an immune modulator
Steroid side effects
Maintains endothelial integrity Inhibits iNOS
Muscle wasting and weakness Increased risks of secondary infection Poor wound healing Glycaemic effects
Maintains vascular tone Maintains responses to adrenaline
The endothelium9 The endothelium is a key component in the sepsis process. It is an extremely active organ in terms of the production and metabolism of numerous inflammatory and vascular mediators. It also acts as a cellular interface, a regulator of vascular tone, and a dynamic barrier in terms of its ability to alter its permeability. Much of the tissue damage and organ dysfunction seen in severe sepsis is related to interaction between activated
Fluid retention Table 1
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leucocytes and the endothelium. Cytokines stimulate the production of adhesion molecules by both the cell groups, which allows for margination and subsequent transportation of leucocytes into tissues. Some of these mediators are also released into the systemic circulation and can be measured. Examples include I-CAM (intracellular adhesion molecule-1), V-CAM (vascular cell adhesion molecule) and selectins. Control of vascular tone is via endothelial derived mediators. These include prostacyclin (a vasodilator), endothelin (a vasoconstrictor) and probably most importantly nitric oxide (NO). Many forms of nitric oxide synthetase (NOS) have been identified e some are involved in physiological vasomotor and neuronal activity. A subgroup of the enzyme exists within endothelial, smooth muscle cells and leucocytes, which is induced in severe sepsis by cytokines. The nitric oxide produced is a potent vasodilator and is now felt to be one of the main mediators of the prolonged hypotension seen in sepsis. Nitric oxide also inhibits mitochondrial respiration and via the production of unstable free radicals is cellulotoxic.10 It would seem sensible to develop an inhibitor of NO for use in sepsis. Inhibitors of NOS have been produced and withdrawn due to excess mortality. This may be explained by the potential concerns that it would interfere with overall microcirculatory flow and hence be detrimental to regional perfusion. Methylene blue has been shown to increase blood pressure in patients with sepsis by inhibiting production of NO, its value in clinical practice however is yet to be determined.11
Definitions in sepsis Invasion of microorganisms into normally sterile place
Bacteraemia SIRS Sepsis Severe sepsis
Viable bacteria in bloodstream See Box 1 SIRS resulting from documented infection Sepsis associated with organ dysfunction, hypoperfusion or hypotension Severe sepsis with hypotension (systolic BP <90 or >40 mmHg reduction from baseline), in absence of other causes despite adequate fluid resuscitation
Septic shock
Table 2
Haemodynamics and the microcirculation (Figure 3) The most prominent haemodynamic feature of severe sepsis is peripheral vasoplegia as mediated by the numerous inflammatory mediators discussed above. Hypovolaemia however may coexist due to multiple factors including inadequate intake and increased losses during the primary illness. This can lead to a reduction in cardiac preload and a negative impact on cardiac function. As such ensuring adequate vascular filling is paramount in the initial phases of sepsis management. Classically sepsis is associated with a high cardiac output state as a result of the marked vasoplegia causing a reduced systemic vascular resistance. As blood pressure is a product of cardiac output and systemic vascular resistance, to maintain blood pressure the cardiac output must increase and the heart works harder. It is increasingly recognized however that many of the inflammatory mediators described above can contribute to myocardial depression. This may also be linked with local cardiac tissue injury from hypoxaemia and acidosis as the result of the systemic sepsis. It is also further confounded by the fact that a patient’s cardiac response to severe sepsis will also be influenced by underlying co-morbidities. The importance of this is that a reduced blood pressure in a septic patient may be multifactorial in origin, and the treatment required needs careful examination of the patient. Assessment of these haemodynamic features is increasingly being aided by the use of bedside echocardiography in intensive care practice.14 The primary goal of the circulation is to deliver necessary substrates to the tissues for metabolism. Sepsis results in a breakdown of this system which culminates in organ failures. Most vital organs are known to physiologically autoregulate blood flow within a given blood pressure range. This range is dictated by the patient’s usual resting blood pressure. However these systems may fail in severe sepsis due to the marked inflammatory response and flow may become more passive (Figure 4). Despite being a commonly used marker of the adequacy of tissue perfusion systemic blood pressure is in fact probably a very poor marker of local tissue perfusion, which is very dependent on the microcirculation in that area. Marked microcirculatory changes are seen in sepsis not only due to inflammatory responses but also coagulation-related abnormalities.
Redox Sepsis is a condition in which there is a marked oxidative stress. Activated leucocytes and cells damaged by ischaemic/reperfusion insults can release large bursts of reactive nitrogen compounds and free radicals that can be directly cellulotoxic, and cause damage to DNA and mitochondria. Physiologically there are numerous agents that reduce the potential formation of these substances and resist oxidative stress. These include vitamins C and E, glutathione and transferrin. The concentration of antioxidants in the plasma of patients with severe sepsis who do not survive has been shown to be lower than those who do; the effect of antioxidant replacement therapies however is yet to be defined in severe sepsis.12 Genomics This is an area within its infancy within medicine. It is likely however that it will contribute to furthering our knowledge base in the area of severe sepsis. To date small studies have suggested that some genetic polymorphisms of common inflammatory mediators may indicate an increased susceptibility towards severe sepsis.13 Larger scale trials are needed to map this information out further to see if any meaningful clinical tools can be made to predict outcome or perhaps direct therapy. It is likely however that this will be a very challenging and intricate area with a multitude of variables to contend with.
Sepsis e the physiological changes The above discussion outlines briefly the complex molecular interactions involved in cases of severe sepsis. To appreciate how this culminates into the pathophysiology seen it is useful to revise the commonly used definitions in this field (Table 2).
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Haemodynamics in sepsis
Vasoplegia
BP = CO x SVR
Microcirculatory dysfunction Failure of autoregulation, clotting, regional flow defects, permeability and oedema
Lactate Inflammatory mediators
Organ dysfunction Cell nucleus
Mitochondrion
Tissue dysoxia Mitochondrial respiratory failure
Figure 3
Inflammatory mediators and local tissue damage result in the release of tissue factor which activates the coagulation cascade. This causes platelet microaggregation and thrombosis which in turn perpetuates further microcirculatory injury and local tissue perfusion abnormalities. Disseminated intravascular coagulation represents the extreme unregulated version of this process whereby marked systemic coagulation occurs to an extent where the consumption of coagulation products also results in bleeding. It is associated unsurprisingly with a very poor prognosis. Some anti-inflammatory/anti-thrombotic mediators, such as protein C,
exist endogenously to limit these coagulation effects in sepsis. Indeed for a period of time recently it was recognized that in severe sepsis levels of protein C were reduced. Activated protein C was marketed as a treatment for the most severe cases of sepsis after initial promising trials suggesting mortality benefit. Followup trials have however failed to reproduce these effects and in face of the significant bleeding risk associated with the product it has now been removed from the market.15 Therefore during severe sepsis marked vascular changes are seen including vasodilatation and poor distribution of regional blood flow due to obstructed capillaries. There is also an increased permeability leading to tissue oedema, and increased blood viscosity which further affects regional flows and promotes coagulation. All these local vascular changes within organs can lead to tissue damage. Alongside the mitochondrial respiratory failure described earlier, it also contributes to the reduced tissue oxygen extraction seen in these patients. This means that even if oxygen delivery is adequate it may not be utilized appropriately by cells. These factors promote the production of lactate an anaerobic metabolite which is commonly but not exclusively raised in severe sepsis. Lactate is constantly produced physiologically by muscles and erythrocytes and circulates until metabolized by the liver, kidneys and heart. This Cori cycle (Figure 5) maintains lactate levels normally less than 2 mmol/litre. In sepsis the plasma lactate level is dictated by the conditions described above, which promote anaerobic metabolism and also by reduced metabolism (Figure 5). In sepsis other organs including the lungs may become a significant source of lactate production. Lactic acid can contribute to the severe systemic acidosis seen in sepsis, which can affect numerous physiological functions and contribute to myocardial dysfunction and increased respiratory drive. Despite high lactate levels signifying a worse prognosis and trends in lactate levels being useful in monitoring responses to treatment, lactate does have its limits in the setting of sepsis (Figure 5).
Autoregulation and passive flows
Blood flow
Autoregulation
Autoregulation Passive flow Blood pressure
Figure 4
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Lactate and sepsis
Glucose
Pyruvate
Glucose
Cori cycle
ATP L-Lactate
ATP L-Lactate te
Factors affecting metabolism Metabolic capacity dictated by plasma concentration (progressively decreases as levels increase), liver function and perfusion
Factors promoting production Rapid increases in metabolic rate or oxygen delivery/mitochondrial dysfunction including: • Ischaemia • Hypoxia • Poor perfusion • Calecholamines • Thiamine deficiency • Drugs • Seizures
• Lactate is constantly produced and metabolised via the Cori cycle to maintain plasma levels less than 2 • In sepsis plasma lactate levels reflect balances between its production which is increased due to anaerobic conditions and cytokine-induced mitochondrial failure as well as failure to clear levels due to factors listed above • It is not diagnostic of sepsis but rather reflects the changes in microcirculatory/ mitochondrial function that leads to imbalances in the normal Cori cycle • High lactate levels are of prognostic significance in sepsis – likely reflecting the extent of the underlying defects and responses to treatment • Lactate has its limits – it can be raised in a multitude of conditions, some of which may co-exist with sepsis; adrenaline, β agonists and certain drugs used in treating septic patients can raise lactate levels limiting its utility as a marker; local perfusion abnormalities may be present even in the face of relatively normal lactate levels, and significant abnormalities may already be present before lacate levels start to rise
Figure 5
hepatosplenic circulation (loss of mucosal integrity, systemic endotoxinaemia, intolerance of feeds, diarrhoea, gastrointestinal haemorrhage) heart (cardiac dysfunction) liver (transaminitis, jaundice) peripheral nervous syndrome (critical illness weakness) metabolic responses (increased insulin resistance, hypermetabolism, catabolism). The treatment of severe sepsis is usually a prolonged course of developing organ failures even after the initial insult has been dealt with. This pattern of multi-organ dysfunction can be selfperpetuating in cases whereby one insult leads to another; for example the extreme catabolism that occurs during the inflammatory phase results in muscle weakness, prolonged ventilation, poor mobility and poor wound healing all of which risks further
Overall therefore despite maintaining a systemic blood pressure in septic patients, local tissue microcirculatory dysfunction and tissue dysoxia may persist. These changes can lead to tissue ischaemia, inflammation, apoptosis, and reperfusion injury that may ultimately culminate in organ dysfunction. Multi-organ dysfunction syndrome and sepsis In severe sepsis every organ system is susceptible to the insults described above. Depending on the degree of insult this can culminate in organ dysfunction. Commonly affected organs include: lungs (acute lung injury) kidneys (oliguria and acute kidney injury) central nervous system (septic encephalopathy, or encephalopathies relating to other organ failures)
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2 Bone RC. Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 1996; 24: 1125e8. 3 Wang H, Chen B. Diagnostic role of soluble triggering receptor expressed on myeloid cell-1 in patients with sepsis. World J Emerg Med 2011; 2: 190e4. 4 Hinds C, Watson D. Shock, sepsis and multi-organ failure. In: Hinds C, Watson D, eds. Intensive care a concise textbook. 3rd edn. Edinburgh: Elsevier, 2008; 81e139. 5 Aytug S. Euthyroid sick syndrome. http://emedicine.medscape.com/ article/118651-overview#a0104 (accessed 10 Mar 2012). 6 Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin. J Am Med Assoc 2000; 283: 1038e45. 7 Bone RC, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. New Engl J Med 1987; 317: 653e8. 8 Annane D, Bellissant PE, Bollaert PE, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. Br Med J 2004; 329: 480. 9 Aird W. The role of the endothelium in severe sepsis and multi-organ dysfunction syndrome. Blood 2003; 101: 3765e77. 10 Hauser B, Bracht H, Matejovic M, Radermacher P, Venkatesh B. Nitric oxide synthetase inhibition in sepsis? Lessons learned from largeanimal studies. Anaesth Analg 2005; 101: 488e98. 11 Kwok ES. Use of methylene blue in sepsis: a systematic review. J Int Care Med 2006; 21: 359e63. 12 Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK. Plasma antioxidant potential in severe sepsis: a comparison of survivors and non-survivors. Crit Care Med 1996; 24: 1179e83. 13 Stuber F, Peterson M, Bokelmann F, et al. A genomic polymorphism within the tumour necrosis factor locus influences plasma tumour necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24: 381e4. 14 Vieillard-Baron A, Charron C, Chergui K, Peyrouset O, Jardin F. Bedside echocardiographic evaluation of haemodynamics in sepsis: is a qualitative evaluation sufficient? Int Care Med 2006; 32: 1547e52. 15 National Institute for Health and Clinical Excellence. TA84. Drotrecogin alfa (activated) for severe sepsis. http://publications.nice. org.uk/drotrecogin-alfa-activated-for-severe-sepsis-ta84/importantinformation-about-this-guidance#november-2011 (accessed 2 Mar 2012).
Multi-organ dysfunction in perspective Organ dysfunction and sepsis Primary insult
Further insult
DEATH
Intervention
Organ dysfunction
Recovery
Figure 6
infection and insult. Indeed one insult may lead to a clinical intervention, which results in a further insult. For example the patient with sepsis and respiratory failure who develops a ventilator associated pneumonia, or receives a drug which causes renal/hepatic impairment (Figure 6). Severe sepsis carries a considerable mortality due to the myriad of potential insults and processes involved. Survivors of severe sepsis and intensive care require a significant period of rehabilitation and have persisting increased mortality and morbidity for a number of years after the initial insult. This is due to a range of physical, psychological and social morbidities that linger on after hospital treatment. Recovery can be a slow process and certainly does not end after successful intensive care treatment. A
REFERENCES 1 Ferrante A. Activation of neutrophils by interleukins-1 and -2 and tumour necrosis factors. Immunol Ser 1992; 57: 417e36.
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A magic bullet for sepsis e a needle in a haystack or barking up the wrong tree?
side effects with the potential for further activation of immunological and host responses, leading to additional organ dysfunctions and failures.
Sepsis at a molecular level Microbial triggering (Figure 1) In sepsis, microorganisms release chemicals which interact with the host’s immune system, triggering host T-cell responses which in turn enhance activation of intracellular nuclear transcription factors culminating in a release of numerous inflammatory mediators. Some of the more recognized microbial triggers are described below. Endotoxins are lipopolysaccharides (LPS) released from the cell walls of Gram-negative bacteria. These avidly bind to lipopolysaccharide- binding protein, an acute phase reactant produced by the host, with the resulting complex activating macrophages, T-cells and opsonization processes. Endotoxin has also been detected in cases of Gram-positive sepsis. This may be related to injury to the gut mucosa during severe sepsis of any cause, and translocation of Gram-negative organisms into the systemic circulation. Gram-positive organisms however also release molecules such as peptidoglycans and lipoteichoic acid. These molecules can also activate the host’s immune system via interaction with T-cells. Also some bacteria can release exotoxins (superantigens) that can activate host responses directly without specific mediation by immunological cells (e.g. toxic shock syndrome); exotoxins (proteases and porins) that can directly cause host cell damage; or exotoxins (e.g. tetanus) that directly mediate the disease process. Fungal cell wall material can also stimulate the host’s innate immunity. Anti-endotoxin therapies include non-specific polyclonal antiserums, monoclonal therapies directed against endotoxins, and endotoxin binding proteins. Although some trials have suggested potential benefit with the use of these agents, the biggest downfall in their use is initiating therapy at an early enough phase of confirmed gram negative sepsis to gain benefit.
P adraig Headley Conn Russell
Abstract Severe sepsis causes significant morbidity and mortality and constitutes a considerable burden on the National Health Service. Our understanding of the pathophysiology, molecular processes and genomics is gradually improving. There is increasing attention being paid on trying to find a novel targeted treatment for sepsis. However, no agent to date has weathered clinical trials and analyses. One that came close was activated protein C, but it has now been removed from the market due to lack of clinical efficacy. The purpose of this article is to explore current theories underpinning the scientific basis and pathophysiology of sepsis, and to link it to the search for targeted therapies.
Keywords Critical care; infection; multi-organ failure; pathophysiology; sepsis; systemic inflammatory response
Sepsis/systemic inflammatory response Systemic inflammatory response syndrome (SIRS) encompasses a collection of clinical findings resulting from harmful insults (Box 1). SIRS and sepsis are not synonymous, but rather sepsis is just one common insult resulting in SIRS. Infection is simply the invasion of tissue by microorganisms which then multiply and may or may not have numerous toxic consequences. Sepsis reflects the systemic consequences of infection and is inherently linked to the microbiological activity and its interaction with the host responses. Sepsis is a complex pathological process involving the activation of the innate immune system. As with any immunological process numerous mediators, receptors and chemistry are involved. Genomics is likely to have an impact in these processes, with differing polymorphisms potentially influencing the type and magnitude of effects seen. Dissemination of these responses and their potential dysregulation results in sepsis. Even after the main insult has been eradicated, multi-organ dysfunction can persist. Supportive treatments and interventions used in the management of severe sepsis have a range of
Cytokines: SIRS versus compensatory anti-inflammatory responses (CARS) Once triggered, the host’s immune system will release numerous inflammatory mediators called cytokines. These are polypeptides released by macrophages, T-cells and endothelial cells in response to sepsis and other insults. Tumour necrosis factor (TNF) is one of the first cytokines to be released and is a potent neutrophil activator. Interleukin (IL) -1 is also released and acts synergistically. IL-6 stimulates acute phase reactants and potentates myocardial dysfunction in sepsis. It also is involved in stimulating a fever, cachexia and anaemia. These mediators stimulate many of the features of a systemic inflammatory response. Conversely other anti-inflammatory mediators exist including IL-10 and IL-4. Endogenous inhibitors of the pro-inflammatory mediators are also recognized. The host can also down-regulate inflammatory responses by for example shedding receptors. This is seen with TNF whereby the cell wall receptors are shed and released into circulation as soluble TNF receptors to mop up
draig Headley MB BCH BAO MRCP PgDip(Critical Care) is a Specialty Registrar Pa in Acute Internal Medicine and Intensive Care Medicine at the Ulster Hospital, Belfast, Ireland. Conflicts of interest: none declared. Conn Russell FCA FRCA FICM DIBICM is a Consultant in Anaesthesia and Intensive Care Medicine at the Ulster Hospital, Belfast, Ireland. Conflicts of interest: none declared.
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therefore be the answer. Also with regards studying these mediators during the course of sepsis we cannot even be certain if circulating levels reflect actual local biological activity. This also tempers moves towards directed pharmacological therapies in this area.
Systemic inflammatory response syndrome criteria Temp >38; <36 C Heart rate >90 bpm Respiratory rate >20 bpm Leucocytes >12 or <4 cells/cm3
C C C C
Acute phase reactants An acute phase reactant is a protein, the concentration of which increases or decreases significantly during a systemic insult such as sepsis. It is likely that some proteins decrease in concentration to supply amino acid demand for others (e.g. albumin). A fall in serum albumin is a common sign seen in severe sepsis and serves as a prognostic marker. Some acute phase reactants however are likely to have a physiological role during the insult (e.g. LPS-binding protein binds endotoxins). C-reactive protein is a commonly measured acute phase reactant which acts physiologically to promote opsonization. Of note it is neither specific nor diagnostic of sepsis. An immunoglobulin receptor called sTREM-1 (soluble triggering receptor expressed on myeloid cells-1) can now be measured in the serum, and may prove more specific in identifying infection as a cause for SIRS.3 Other acute phase reactants include serum amyloid A (which is of uncertain importance at present but is linked with secondary amyloidosis in chronic infections); and transferrin (increases of which may help with iron binding and reducing oxidative stresses during insults). The complement pathway is also a complex example of interlinked acute phase reactants with immunological functions. The production of multiple acute phase reactants is likely to contribute to the marked catabolism seen in sepsis, and the development of conditional deficiencies in amino acids such as glutamine due to the cellular requirements to produce some of these proteins in high quantities.
Box 1
and inactivate circulating TNF.1 Processes like this act as a compensatory anti-inflammatory response (CARS).2 Overall this is a very complex and incompletely understood process, which may explain why pharmacological therapies aimed here have yet to show any promise. Certainly there is a process by which, when triggered, the host mounts an inflammatory cascade which is then regulated by antiinflammatory processes to achieve resolution. Harmonizing these conflicting processes to achieve the correct balance intuitively seems crucial for recovery from sepsis. Imbalances due to over- or under-activity of either arm will likely result in poor outcome (Figure 2). It also means that at differing times within the same patient, and to differing extents in different patients, one arm may be more active than the other. Targeting therapy against one mediator across this whole population may not
Microbial triggering Triggering Pathogen-associated molecules Endotoxins Peptidoglycans Fungal cell walls
Exotoxins and superantigens
Prostaglandins4 Prostaglandins and leukotrienes are released from the enzymatic degradation of cell membrane lipids by phospholipases, cyclooxygenases and lipoxygenases during sepsis and contribute to the SIRS/CARS balance. There is potential for these to be further metabolized into numerous other mediators which have numerous effects. The net physiological effect will depend on the nature of the released mix and its overall biologically activity. Examples include prostacyclin which is a potent vasodilator and platelet inhibitor. Conversely thromboxane causes vasoconstriction and platelet aggregation. Platelet-activating factor is another example which causes hypotension, platelet aggregation and vascular permeability. These are many of the features seen in severe sepsis. Prostaglandin and bradykinin inhibitors, alongside non-steroidal anti-inflammatory drugs, have so far failed to show any benefit in the treatment of severe sepsis.
Immune system
Cytotoxic
RESPONSE
Inflammatory responses
Hypothalamusepituitary axis (HPA) Endocrine mediated changes within the host are well recognized in many forms of insult/stress. Sepsis is no different in this respect. While many of these processes are likely to be physiological reactions to help mitigate the extent of the insult, there has been much interest in exploring how some of these processes may in fact be detrimental or could be manipulated in cases of sepsis. The HPA acts as the conductor of the endocrine system and is directly activated in severe sepsis by the systemic release
Gram-negative bacteria – endotoxin
Figure 1
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Systemic inflammatory response syndrome (SIRS) versus compensatory anti-inflammatory responses (CARS) Balancing inflammatory and anti-inflammatory mediators in sepsis Hyper-responsive, persistent inflammation and organ damage, death/recovery
SIRS
Hypo-responsive, nocosomial infection, failure to resolve death/recovery CARS Figure 2
of cytokines, which result in the release of corticotropic-releasing hormone, adenocorticotropic hormone, growth hormone, prolactin and vasopressin; as well as endorphins which are shown to have increasing immunomodulatory as well as analgesic properties. The acute phase response is also relevant here as many of the endogenous hormone-binding proteins change their concentration in severe sepsis. Changes in the systemic binding of hormones will also alter their peripheral biologically activity. These factors make the standard measurement and interpretation of hormone profiles very difficult in these cases. This is evident in the non-thyroidal illness syndrome or sick euthyroid syndrome.5 In this case there appears to be a downregulation of thyroid function on testing, which is of uncertain clinical significance at present. Certainly however these hormonal changes will physiologically regulate cellular metabolics in severe sepsis; and the extent to which they do or do not occur is likely to be significant. The most discussed of the hormonal processes in sepsis is probably the adrenocortical axis. Corticosteroids are well recognized as immune modulators and many of these features seem attractive in the setting of sepsis
(Table 1). In any form of shock, cortisol levels typically rise, with a loss of the natural circadian rhythm. A reduction in cortisol binding globulin also occurs with a rise in free cortisol levels. The extent of the rise in cortisol has been studied in sepsis to see if it is linked to prognosis, with a mixed outcome between the studies. It has been suggested however that patients with high basal cortisol levels, with or without a blunted response to stimulation, have an increased mortality in sepsis.6 Whether this is a cause for increased mortality or simply the effect of being ‘more ill’ is yet to be determined. Also the factors driving these changes, between different patients, are yet to be established. There was previous enthusiasm in the early 1980s for the use of therapeutic dose steroids as immunosuppressants in severe sepsis. This has since been shown to be of no benefit or even detrimental except in predefined clinical conditions.7 Enthusiasm has since moved towards the use of physiological doses of steroids in sepsis. Studies have shown that the use of low dose hydrocortisone in patients who are vasopressor dependent with sepsis have reduced overall vasopressor requirements.8 This however does not translate into a mortality benefit. The endocrine story as with many areas in severe sepsis remains incompletely understood. Studies looking at altering hormonal balance to improve mortality in sepsis face numerous challenges including the cause-effect analogy, patient selection and treatment timing factors, and the difficulties of interpreting routine endocrine tests in this subgroup.
Steroids in sepsis Steroids as an immune modulator
Steroid side effects
Maintains endothelial integrity Inhibits iNOS
Muscle wasting and weakness Increased risks of secondary infection Poor wound healing Glycaemic effects
Maintains vascular tone Maintains responses to adrenaline
The endothelium9 The endothelium is a key component in the sepsis process. It is an extremely active organ in terms of the production and metabolism of numerous inflammatory and vascular mediators. It also acts as a cellular interface, a regulator of vascular tone, and a dynamic barrier in terms of its ability to alter its permeability. Much of the tissue damage and organ dysfunction seen in severe sepsis is related to interaction between activated
Fluid retention Table 1
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leucocytes and the endothelium. Cytokines stimulate the production of adhesion molecules by both the cell groups, which allows for margination and subsequent transportation of leucocytes into tissues. Some of these mediators are also released into the systemic circulation and can be measured. Examples include I-CAM (intracellular adhesion molecule-1), V-CAM (vascular cell adhesion molecule) and selectins. Control of vascular tone is via endothelial derived mediators. These include prostacyclin (a vasodilator), endothelin (a vasoconstrictor) and probably most importantly nitric oxide (NO). Many forms of nitric oxide synthetase (NOS) have been identified e some are involved in physiological vasomotor and neuronal activity. A subgroup of the enzyme exists within endothelial, smooth muscle cells and leucocytes, which is induced in severe sepsis by cytokines. The nitric oxide produced is a potent vasodilator and is now felt to be one of the main mediators of the prolonged hypotension seen in sepsis. Nitric oxide also inhibits mitochondrial respiration and via the production of unstable free radicals is cellulotoxic.10 It would seem sensible to develop an inhibitor of NO for use in sepsis. Inhibitors of NOS have been produced and withdrawn due to excess mortality. This may be explained by the potential concerns that it would interfere with overall microcirculatory flow and hence be detrimental to regional perfusion. Methylene blue has been shown to increase blood pressure in patients with sepsis by inhibiting production of NO, its value in clinical practice however is yet to be determined.11
Definitions in sepsis Invasion of microorganisms into normally sterile place
Bacteraemia SIRS Sepsis Severe sepsis
Viable bacteria in bloodstream See Box 1 SIRS resulting from documented infection Sepsis associated with organ dysfunction, hypoperfusion or hypotension Severe sepsis with hypotension (systolic BP <90 or >40 mmHg reduction from baseline), in absence of other causes despite adequate fluid resuscitation
Septic shock
Table 2
Haemodynamics and the microcirculation (Figure 3) The most prominent haemodynamic feature of severe sepsis is peripheral vasoplegia as mediated by the numerous inflammatory mediators discussed above. Hypovolaemia however may coexist due to multiple factors including inadequate intake and increased losses during the primary illness. This can lead to a reduction in cardiac preload and a negative impact on cardiac function. As such ensuring adequate vascular filling is paramount in the initial phases of sepsis management. Classically sepsis is associated with a high cardiac output state as a result of the marked vasoplegia causing a reduced systemic vascular resistance. As blood pressure is a product of cardiac output and systemic vascular resistance, to maintain blood pressure the cardiac output must increase and the heart works harder. It is increasingly recognized however that many of the inflammatory mediators described above can contribute to myocardial depression. This may also be linked with local cardiac tissue injury from hypoxaemia and acidosis as the result of the systemic sepsis. It is also further confounded by the fact that a patient’s cardiac response to severe sepsis will also be influenced by underlying co-morbidities. The importance of this is that a reduced blood pressure in a septic patient may be multifactorial in origin, and the treatment required needs careful examination of the patient. Assessment of these haemodynamic features is increasingly being aided by the use of bedside echocardiography in intensive care practice.14 The primary goal of the circulation is to deliver necessary substrates to the tissues for metabolism. Sepsis results in a breakdown of this system which culminates in organ failures. Most vital organs are known to physiologically autoregulate blood flow within a given blood pressure range. This range is dictated by the patient’s usual resting blood pressure. However these systems may fail in severe sepsis due to the marked inflammatory response and flow may become more passive (Figure 4). Despite being a commonly used marker of the adequacy of tissue perfusion systemic blood pressure is in fact probably a very poor marker of local tissue perfusion, which is very dependent on the microcirculation in that area. Marked microcirculatory changes are seen in sepsis not only due to inflammatory responses but also coagulation-related abnormalities.
Redox Sepsis is a condition in which there is a marked oxidative stress. Activated leucocytes and cells damaged by ischaemic/reperfusion insults can release large bursts of reactive nitrogen compounds and free radicals that can be directly cellulotoxic, and cause damage to DNA and mitochondria. Physiologically there are numerous agents that reduce the potential formation of these substances and resist oxidative stress. These include vitamins C and E, glutathione and transferrin. The concentration of antioxidants in the plasma of patients with severe sepsis who do not survive has been shown to be lower than those who do; the effect of antioxidant replacement therapies however is yet to be defined in severe sepsis.12 Genomics This is an area within its infancy within medicine. It is likely however that it will contribute to furthering our knowledge base in the area of severe sepsis. To date small studies have suggested that some genetic polymorphisms of common inflammatory mediators may indicate an increased susceptibility towards severe sepsis.13 Larger scale trials are needed to map this information out further to see if any meaningful clinical tools can be made to predict outcome or perhaps direct therapy. It is likely however that this will be a very challenging and intricate area with a multitude of variables to contend with.
Sepsis e the physiological changes The above discussion outlines briefly the complex molecular interactions involved in cases of severe sepsis. To appreciate how this culminates into the pathophysiology seen it is useful to revise the commonly used definitions in this field (Table 2).
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Haemodynamics in sepsis
Vasoplegia
BP = CO x SVR
Microcirculatory dysfunction Failure of autoregulation, clotting, regional flow defects, permeability and oedema
Lactate Inflammatory mediators
Organ dysfunction Cell nucleus
Mitochondrion
Tissue dysoxia Mitochondrial respiratory failure
Figure 3
Inflammatory mediators and local tissue damage result in the release of tissue factor which activates the coagulation cascade. This causes platelet microaggregation and thrombosis which in turn perpetuates further microcirculatory injury and local tissue perfusion abnormalities. Disseminated intravascular coagulation represents the extreme unregulated version of this process whereby marked systemic coagulation occurs to an extent where the consumption of coagulation products also results in bleeding. It is associated unsurprisingly with a very poor prognosis. Some anti-inflammatory/anti-thrombotic mediators, such as protein C,
exist endogenously to limit these coagulation effects in sepsis. Indeed for a period of time recently it was recognized that in severe sepsis levels of protein C were reduced. Activated protein C was marketed as a treatment for the most severe cases of sepsis after initial promising trials suggesting mortality benefit. Followup trials have however failed to reproduce these effects and in face of the significant bleeding risk associated with the product it has now been removed from the market.15 Therefore during severe sepsis marked vascular changes are seen including vasodilatation and poor distribution of regional blood flow due to obstructed capillaries. There is also an increased permeability leading to tissue oedema, and increased blood viscosity which further affects regional flows and promotes coagulation. All these local vascular changes within organs can lead to tissue damage. Alongside the mitochondrial respiratory failure described earlier, it also contributes to the reduced tissue oxygen extraction seen in these patients. This means that even if oxygen delivery is adequate it may not be utilized appropriately by cells. These factors promote the production of lactate an anaerobic metabolite which is commonly but not exclusively raised in severe sepsis. Lactate is constantly produced physiologically by muscles and erythrocytes and circulates until metabolized by the liver, kidneys and heart. This Cori cycle (Figure 5) maintains lactate levels normally less than 2 mmol/litre. In sepsis the plasma lactate level is dictated by the conditions described above, which promote anaerobic metabolism and also by reduced metabolism (Figure 5). In sepsis other organs including the lungs may become a significant source of lactate production. Lactic acid can contribute to the severe systemic acidosis seen in sepsis, which can affect numerous physiological functions and contribute to myocardial dysfunction and increased respiratory drive. Despite high lactate levels signifying a worse prognosis and trends in lactate levels being useful in monitoring responses to treatment, lactate does have its limits in the setting of sepsis (Figure 5).
Autoregulation and passive flows
Blood flow
Autoregulation
Autoregulation Passive flow Blood pressure
Figure 4
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Lactate and sepsis
Glucose
Pyruvate
Glucose
Cori cycle
ATP L-Lactate
ATP L-Lactate te
Factors affecting metabolism Metabolic capacity dictated by plasma concentration (progressively decreases as levels increase), liver function and perfusion
Factors promoting production Rapid increases in metabolic rate or oxygen delivery/mitochondrial dysfunction including: • Ischaemia • Hypoxia • Poor perfusion • Calecholamines • Thiamine deficiency • Drugs • Seizures
• Lactate is constantly produced and metabolised via the Cori cycle to maintain plasma levels less than 2 • In sepsis plasma lactate levels reflect balances between its production which is increased due to anaerobic conditions and cytokine-induced mitochondrial failure as well as failure to clear levels due to factors listed above • It is not diagnostic of sepsis but rather reflects the changes in microcirculatory/ mitochondrial function that leads to imbalances in the normal Cori cycle • High lactate levels are of prognostic significance in sepsis – likely reflecting the extent of the underlying defects and responses to treatment • Lactate has its limits – it can be raised in a multitude of conditions, some of which may co-exist with sepsis; adrenaline, β agonists and certain drugs used in treating septic patients can raise lactate levels limiting its utility as a marker; local perfusion abnormalities may be present even in the face of relatively normal lactate levels, and significant abnormalities may already be present before lacate levels start to rise
Figure 5
hepatosplenic circulation (loss of mucosal integrity, systemic endotoxinaemia, intolerance of feeds, diarrhoea, gastrointestinal haemorrhage) heart (cardiac dysfunction) liver (transaminitis, jaundice) peripheral nervous syndrome (critical illness weakness) metabolic responses (increased insulin resistance, hypermetabolism, catabolism). The treatment of severe sepsis is usually a prolonged course of developing organ failures even after the initial insult has been dealt with. This pattern of multi-organ dysfunction can be selfperpetuating in cases whereby one insult leads to another; for example the extreme catabolism that occurs during the inflammatory phase results in muscle weakness, prolonged ventilation, poor mobility and poor wound healing all of which risks further
Overall therefore despite maintaining a systemic blood pressure in septic patients, local tissue microcirculatory dysfunction and tissue dysoxia may persist. These changes can lead to tissue ischaemia, inflammation, apoptosis, and reperfusion injury that may ultimately culminate in organ dysfunction. Multi-organ dysfunction syndrome and sepsis In severe sepsis every organ system is susceptible to the insults described above. Depending on the degree of insult this can culminate in organ dysfunction. Commonly affected organs include: lungs (acute lung injury) kidneys (oliguria and acute kidney injury) central nervous system (septic encephalopathy, or encephalopathies relating to other organ failures)
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2 Bone RC. Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 1996; 24: 1125e8. 3 Wang H, Chen B. Diagnostic role of soluble triggering receptor expressed on myeloid cell-1 in patients with sepsis. World J Emerg Med 2011; 2: 190e4. 4 Hinds C, Watson D. Shock, sepsis and multi-organ failure. In: Hinds C, Watson D, eds. Intensive care a concise textbook. 3rd edn. Edinburgh: Elsevier, 2008; 81e139. 5 Aytug S. Euthyroid sick syndrome. http://emedicine.medscape.com/ article/118651-overview#a0104 (accessed 10 Mar 2012). 6 Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin. J Am Med Assoc 2000; 283: 1038e45. 7 Bone RC, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. New Engl J Med 1987; 317: 653e8. 8 Annane D, Bellissant PE, Bollaert PE, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. Br Med J 2004; 329: 480. 9 Aird W. The role of the endothelium in severe sepsis and multi-organ dysfunction syndrome. Blood 2003; 101: 3765e77. 10 Hauser B, Bracht H, Matejovic M, Radermacher P, Venkatesh B. Nitric oxide synthetase inhibition in sepsis? Lessons learned from largeanimal studies. Anaesth Analg 2005; 101: 488e98. 11 Kwok ES. Use of methylene blue in sepsis: a systematic review. J Int Care Med 2006; 21: 359e63. 12 Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK. Plasma antioxidant potential in severe sepsis: a comparison of survivors and non-survivors. Crit Care Med 1996; 24: 1179e83. 13 Stuber F, Peterson M, Bokelmann F, et al. A genomic polymorphism within the tumour necrosis factor locus influences plasma tumour necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24: 381e4. 14 Vieillard-Baron A, Charron C, Chergui K, Peyrouset O, Jardin F. Bedside echocardiographic evaluation of haemodynamics in sepsis: is a qualitative evaluation sufficient? Int Care Med 2006; 32: 1547e52. 15 National Institute for Health and Clinical Excellence. TA84. Drotrecogin alfa (activated) for severe sepsis. http://publications.nice. org.uk/drotrecogin-alfa-activated-for-severe-sepsis-ta84/importantinformation-about-this-guidance#november-2011 (accessed 2 Mar 2012).
Multi-organ dysfunction in perspective Organ dysfunction and sepsis Primary insult
Further insult
DEATH
Intervention
Organ dysfunction
Recovery
Figure 6
infection and insult. Indeed one insult may lead to a clinical intervention, which results in a further insult. For example the patient with sepsis and respiratory failure who develops a ventilator associated pneumonia, or receives a drug which causes renal/hepatic impairment (Figure 6). Severe sepsis carries a considerable mortality due to the myriad of potential insults and processes involved. Survivors of severe sepsis and intensive care require a significant period of rehabilitation and have persisting increased mortality and morbidity for a number of years after the initial insult. This is due to a range of physical, psychological and social morbidities that linger on after hospital treatment. Recovery can be a slow process and certainly does not end after successful intensive care treatment. A
REFERENCES 1 Ferrante A. Activation of neutrophils by interleukins-1 and -2 and tumour necrosis factors. Immunol Ser 1992; 57: 417e36.
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