Septic shock

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system. In 187980, Louis Pasteur showed for the first time that bacteria were present in blood from patients with puerperal septicaemia. One woman survived, leading Pasteur to state that Natura medicatrix won the victory, an opinion consistent with the notion that sepsis is a systemic response to fight off pathogens (panel, figure 1). However, a consensus on the definition of sepsis was reached only a decade ago, 1 and the list of symptoms was updated very recently.2 Sepsis is now defined as infection with evidence of systemic inflammation, consisting of two or more of the following: increased or decreased temperature or leucocyte count, tachycardia, and rapid breathing. Septic shock is sepsis with hypotension that persists after resuscitation with intravenous fluid. Normally, the immune and neuroendocrine systems tightly control the local inflammatory process to eradicate invading pathogens. When this local control mechanism fails, systemic inflammation occurs, converting the infection to sepsis, severe sepsis, or septic shock.

Epidemiology

The yearly incidence of sepsis is 5095 cases per 100 000, and has been increasing by 9% each year.3 This disease accounts for 2% of hospital admissions; roughly 9% of patients with sepsis progress to severe sepsis, and 3% of those with severe sepsis experience septic shock, 4 which accounts for 10% of admissions to intensive care units.5 The occurrence of septic shock peaks in the sixth decade of life.5 Factors that can predispose people to septic shock include cancer, immunodeficiency, chronic organ failure, iatrogenic factors,3,5,6 and genetic factors,7 such as being male,8 non-white ethnic origin in North Americans,3 and polymorphisms in genes that regulate immunity.9

Cause
Infections of the chest, abdomen, genitourinary system, and primary bloodstream cause more than 80% of cases of sepsis.3,5,6 Rates of pneumonia, bacteraemia, and multiple-site infection have increased steadily over time, whereas abdominal infections have remained unchanged and genitourinary infections have decreased.3,5 The occurrence of gram-negative sepsis has diminished over the years to 2530% in 2000. Grampositive and polymicrobial infections accounted for 3050% and 25% of cases, respectively (table 1).3,5,6 The fact that multidrug-resistant bacteria and fungi now cause about 25% of cases is cause for concern. 5,6 Viruses and parasites are identified in 24% of cases, but their frequency could be underestimated. 5 Lastly, cultures are negative in about 30% of cases, mainly in patients with community-acquired sepsis who are treated with antibiotics before admission.

Pathomechanisms

The definition of sepsis is often over-simplified as being the result of exacerbated inflammatory responses. However, pathogenesis involves several factors that interact in a long chain of events from pathogen recognition to overwhelming of host responses.

Patterns and receptors

Matzinger10 redefined immunity by postulating that immune system activity stemmed from recognition of and reaction to internal danger signals, rather than from discrimination between self and non-self molecules. Danger signals also include recognition of exogenous molecules, pathogen-associated molecular patterns, which are surface molecules such as endotoxin (lipopolysaccharide), lipoproteins, outermembrane proteins, flagellin, fimbriae, peptidoglycan, peptidoglycan-associated lipoprotein, and lipoteichoic acid; and internal motifs released during bacterial lysis, such as heat-shock proteins and DNA fragments. These molecules are common to pathogenic, non-pathogenic, and commensal bacteria, making microbial-associated molecular patterns a better term. These patterns are recognised by specific pattern recognition receptors, which induce cytokine expression. These microbial patterns act synergistically with one another, with host mediators, and with hypoxia. Of pattern recognition receptors, the toll-like receptors are characterised by an extracellular leucinerich repeat domain and a cytoplasmic toll-interleukin-1 receptor (TIR) domain that shares considerable homology with the interleukin-1 receptor cytoplasmic domain. Currently, ten toll-like receptors have been described in humans, and the list of their specific microbial ligands is growing. 11 Signal transduction after interaction between microbial-associated molecular patterns and these receptors results in activation of numerous adaptors, some with the TIR domain (myeloid differentiation protein [MyD] 88, TIR domaincontaining adaptor protein, TIR receptor domaincontaining adaptor protein inducing interferon _

[TRIF], and TRIF-related adaptor molecule), and of kinase proteins. MyD88 interacts directly with most toll-like receptors and appears upstream from activation of the transcription nuclear factor-_B. TRIF results in activation of nuclear factor interferon regulatory factor 3, promoting production of interferon _ (figure 2).11 Additionally, molecules in the cytoplasm (MyD88s, interleukin-1 receptor-associated kinase-M, Tollip, suppressor of cytokine signalling 1) or at the cell surface (single immunoglobulin interleukin-1R-related molecule, ST2) negatively control the signalling cascade. Nod1 and Nod2 proteins are intracellular pattern recognition receptors.12 Nod1s ligand is a peptidoglycan fragment that is almost exclusive to gram-negative bacteria. Nod2 detects a different such fragment and also recognises muramyl dipeptide, the smallest bioactive fragment common to all peptidoglycans. Four peptidoglycan recognition proteins (PGRPs), a third family of pattern recognition receptors, have been characterised in people.13 Three are membrane-bound proteins, PGRP-I_, PGRP-I_, and PGRP-L. The fourth is the soluble molecule PGRP-S.

Leucocytes
Sepsis is associated with migration of activated leucocytes from the bloodstream to inflammatory tissues,14 and with intensified bone-marrow production of leucocytes that are released into the blood as newly differentiated or immature cells. Profound changes arise in peripheral-blood lymphocytes 15,16 and monocytes, 17 as well as changes in cell surface markers (eg, chemokine CXC receptor 2, tumour necrosis factor [TNF] receptor p50 and p75, interleukin 1R, C5a receptor, and toll-like receptors 2 and 4). Downregulation of HLA DR expression on monocytes followed lipopolysaccharide challenge in healthy volunteers,18 and in patients with sepsis is mediated by interleukin 1019 and cortisol,20 and is correlated with death.21 Leucocytes release numerous proteases that play a pivotal part in combating infections. For example, compared with controls, mice that have a knockout of the neutrophil-elastase gene are more susceptible to sepsis and death after intraperitoneal gram-negative, but not gram-positive, infection. 22 In people, concentrations of elastase are increased in plasma and bronchoalveolar lavage fluid,23 and might contribute to shock and organ dysfunction, as suggested by experiments using elastase inhibitor24 or mice that have a knockout of an enzyme required for protease maturation25 or a natural protease inhibitor 26. Cell apoptosis in patients with sepsis varies across cell types. It is increased for blood and spleen lymphocytes and spleen dendritic cells, unchanged for spleen macrophages and circulating monocytes, and reduced for blood neutrophils and alveolar macrophages. 27 Apoptosis is also abnormal in the thymic, intestinal, and pulmonary epithelia and in the brain, but not in the endothelium. In animals, glucocorticoids, 28 Fas ligand,29 and TNF30 are the main proapoptotic factors, and caspase

inhibitors or overexpression of B-cell lymphoma/ leukaemia-2, prevent sepsis-induced apoptosis and death.27 In people, the mechanisms and role of apoptosis in the pathogenesis of septic shock remain unclear. Ex-vivo experiments with blood cells from patients have shown blunted cytokine production in response to mitogens with lymphocytes 31 (both T-helper 1 and T helper 2 cytokines),32 and in response to lipopolysaccharide with neutrophils33,34 and monocytes.35 Neutrophils and monocytes from endotoxin-challenged healthy volunteers gave similar results. 36,37 Although interleukin 10 might partly account for sepsis-associated monocyte hyporesponsiveness to lipopolysaccharide, 38 the underlying molecular mechanisms remain to be clarified. Synthesis of TNF induced by lipopolysaccha ride needs activation and nuclear translocation of nuclear factor _B. Thus, alterations in the pathway of this factor could contribute to monocyte deactivation, as suggested by ex-vivo experiments with lipopolysaccharide stimulation of monocytes from patients, which showed upregulation of the inactive form of this factor (homodimer p50p50), and downregulation of the active form (heterodimer p65p50).39 However, other signalling pathways might remain unaltered or even undergo stimulation (eg, p38 mitogen activated protein kinase [MAPK], Sp1 activation), resulting, for example, in enhanced interleukin-10 responses. 40 In mice, blockade of p38 MAPK prevented sepsis-induced monocyte deactivation.41 Numerous negative regulators of toll-likereceptordependent signalling pathways remain to be investigated in sepsis,42 such as the rapid upregulation of interleukin-1 receptor-associated kinase-M in lipopolysaccharideactivated monocytes from patients.43 The terms anergy, immunodepression, or immunoparalysis are commonly used to describe the immune status of septic patients. However, by contrast with the cell response to lipopolysaccharide, production of TNF after stimulation with heat-killed Staphylococcus aureus, Escherichia coli, or muramyl dipeptide was unaltered (unpublished data), suggesting diversified leucocyte responsiveness to microbial agonists. 40 Thus, we propose the term leucocyte reprogramming, the clinical relevance of which remains to be explored.

Epithelium

In mice, bacteria-mediated epithelial-cell apoptosis could contribute to immune defences via activation of the Fas/Fas ligand system.44 However, lipopolysaccharide might alter the epithelial tight junctions in the lung, liver, and gut, thereby promoting bacterial translocation and organ failure.45 Nitric oxide, TNF, interferon _, and high mobility group box 1 (HMGB1) contribute to the functional disruption of epithelial tight junctions.46 Underlying mechanisms might include an inducible NO synthase-associated decrease in expression of the tight junction protein zonula occludens 1, as well as internalisation of the apical junctional complex transmembrane proteins called junction adhesion molecule 1, occludin, and claudin-1/4. 47

Endothelium
Endothelial cells between blood and tissues promote adhesion of leucocytes, which can then migrate into

tissues. On the one hand, experiments with knockout mice48 or animals treated with adhesion moleculespecific antibodies49 suggest that adhesion molecules expressed on leucocytes or endothelial cells (ie, lymphocyte function associated antigen 1, intercellular adhesion molecule 1, endothelial leucocyte adhesion molecule 1, L-selectin, and P-selectin) might contribute to tissue damage. On the other hand, other adhesionmolecule blockade worsened cardiovascular and metabolic functions.50 In patients with sepsis, neutrophils showed an _4-integrindependent increase in the capacity for vascular cellular adhesion molecule 1 binding.51 The therapeutic effect of modulation of leucocyte adhesion to the endothelium remains unexplored in people. Endotoxin and cytokines induce tissue factor expression by monocytes and endothelial cells in healthy volunteers challenged with lipopolysaccharide 52 and in patients with sepsis.53 In animals, protective effects from administration of tissue factor pathway inhibitor or antibodies to tissue factor or from factor VIIa inhibition suggest a link between inflammation and coagulation. In people, no protective effects from administration of this inhibitor have been reported. 54 Coagulation might aggravate inflammation, especially after interaction of the endothelium with thrombin and factor Xa. In a peritonitis model, blockade of coagulation was harmful.55 However, in heterozygous protein-C-deficient mice, disseminated intravascular coagulation was worsened by injection of lipopolysaccharide,56 and, in people, reduction of the concentrations of protein C was associated with downregulation of coagulation.57

Proinflammatory mediators

During the past 15 years, convincing evidence that cytokines protect against infection came from experiments with recombinant proinflammatory cytokinesparticularly TNF, interleukin 1, and interferon _and antibodies to cytokines and with mice that had a knockout for a single cytokine or its receptor. Similar approaches to investigate toxic shock or infection conclusively showed lethal effects of TNF, interleukin 1_, interleukin 12, interleukin 18, interferon _, granulocytemacrophage colony-stimulating factor, macrophage migration inhibitory factor, interferon _, and HMGB1. In people, cytokines are produced in excess and are therefore detectable in blood, where they are normally absent.58 However, the circulating cytokines are merely the tip of the iceberg,59 and cell-associated cytokines can be identified even when amounts in plasma are undetectable.35 Sepsis is associated with increased concentrations of histamine in plasma from mast cells or basophils (or both) after activation of complement pathways with upregulation of anaphylatoxins C3a and C5a.60 Whereas exogenous histamine or selective histamine H2 receptor agonists protect against endotoxin shock, 61,62 anaphylatoxins enhance vascular permeability and smooth muscle contraction, and are chemoattractants for leucocytes. Moreover, compared with wildtype mice, C5deficient mice responded to lipopolysaccharide with

reduced concentrations of TNF and a lower severity index, and antibodies to C5a or C5a receptors prevented death from sepsis.63 By contrast, mice with a knockout for C4, C3, and C3 receptor were more susceptible to endotoxin, and C1 inhibitor protected against death from sepsis.64 Proinflammatory cytokines induce synthesis of phospholipase A2, inducible cyclo-oxygenase, 5-lipoxygenase, and acetyltransferase, which contribute to synthesis of eicosanoids (prostaglandins and leucotrienes) and platelet-activating factor. These factors, acting through specific G-protein-coupled receptors, promote inflammation, altering vasomotor tone and increasing blood flow and vascular permeability. Mice which are deficient in phospholipase A2 receptor65 and inducible cyclo-oxygenase, but not those deficient in 5lipoxygenase, are resistant to endotoxin. However, prostaglandins E2 can also reduce production of TNF. Superoxide anion, which is produced by NADPH oxidase, oxidises and alters proteins and unsaturated fatty acids of phospholipids. However, some oxidised phospholipids can prevent endotoxin-induced inflammation by blocking the interaction between lipopolysaccharide and lipopolysaccharide-binding protein and CD14. 66 Mice that had a knockout for NADPH oxidase compounds were more susceptible to severe infections than mice that did not, although their sensitivity to endotoxin remained unaltered.67 Mice deficient in inducible NO synthase merely exhibit less severe hypotension after lethal endotoxin challenge.67 In people, large amounts of NO are released after endotoxin exposure or cytokine-related stimulation of inducible NO synthase activity in inflamed tissues68 and vessel walls.69 This NO excess contributes to development of microvessel damage, vascular hyporeactivity, and organ dysfunction, probably by induction of apoptosis.69

Anti-inflammatory mediators

Anti-inflammatory cytokines and soluble receptors are produced in large amounts during sepsis. They downregulate production of proinflammatory cytokines and protect animals from sepsis and endotoxininduced shock. These effects are evident for interleukin 10 (although the effects of this cytokine vary with time, dose, and site of expression), for transforming growth factor _, interferon _, and interleukin 4, interleukin 6, and interleukin 13. On the one hand, interleukin 6 induces a broad array of acute-phase proteins that limit inflammation, such as _-1-acid-glycoprotein or Creactive protein. More recently, interleukin-1 receptor antagonist, lipopolysaccharide binding protein, and soluble CD14 were identified as acute-phase proteins. On the other hand, interleukin 6 could induce myocardial depression during meningococcal septicaemia.70 Though large amounts of circulating interleukin-1 receptor antagonist and soluble receptors for TNF have been reported in sepsis, it remains unclear whether these levels are sufficient to counteract proinflammatory cytokines.58 Neuromediators have a major role in control of inflammation (figure 3). Substance P increases cytokine

production, histamine release via basophil and mast-cell degranulation, leucocyte adhesion and chemotaxis, and vascular permeability. Catecholamines interfere with cytokine production in diverse ways. Norepinephrine, via the _2-adrenergic receptor, increases TNF production, 71 whereas epinephrine interaction with the _2-adrenergic receptor decreases such production in vitro72 and in vivo in lipopolysaccharide-challenged healthy volunteers, and also enhances production of interleukin 10.73 Furthermore, epinephrine increases production of interleukin 874 and suppresses production of NO. 75 The antiinflammatory effects of _-agonists are mediated through reduced degradation of I_B_76 and through increased intracellular concentrations of cyclic AMP. Vasoactive intestinal peptide and pituitary adenylate cyclaseactivating peptide are two anti-inflammatory neuropeptides that inhibit cytokine production and protect mice from lipopolysaccharide lethality. 77,78 In rats treated with lipopolysaccharide, vagal nerve stimulation attenuated hypotension and reduced concentrations of TNF in plasma and liver79 through interaction between acetylcholine and the _7 subunit of the nicotinic receptor at the macrophage surface. 80 Finally, _-melanocyte stimulating hormone, another neuromediator expressed in the brain, could lessen inflammation by inhibition of proinflammatory cytokine production.81 Cross-talk between cytokines and neurohormones is the cornerstone of restoration of homoeostasis during stress.82 Production and release of vasopressin and corticotropin-releasing hormone are enhanced by circulating TNF and interleukin 1, interleukin 6, interleukin 2, by locally expressed interleukin 1_ and NO, and by afferent vagal fibres. Moreover, synthesis of cortisol is modulated by locally expressed interleukin 6 and TNF_. Upregulated hormones help maintain cardiovascular homoeostasis and cellular metabolism, and help wall-off foci of inflammation. Impaired endocrine responses to sepsis might result from cytokines, neuronal apoptosis, metabolic and ischaemic derangements in the hypothalamic-pituitary and adrenal glands, and drug administration. 83 Deficiencies in adrenal gland function84 and vasopressin production 69 occur in about a half and a third of septic shock cases, respectively, contributing to hypotension and death. 8486 Other endocrine disorders during sepsis have unclear mechanisms and consequences (table 2).

Genetic polymorphisms

Various genetic polymorphisms are associated with increased susceptibility to infection and poor outcomes. Markers of susceptibility could include single nucleotide polymorphisms of genes encoding cytokines (eg, TNF, lymphotoxin-_, interleukin 10, interleukin 18, interleukin-1 receptor antagonist, interleukin 6, and interferon _), cell surface receptors (eg, CD14, MD2, toll-like receptors 2 and 4, and Fc-gamma receptors II and III), lipopolysaccharide ligand (lipopolysaccharide binding protein, bactericidal permeability increasing protein), mannose-binding lectin, heat shock protein 70, angiotensin I-converting enzyme, plasminogen activator inhibitor, and caspase-12. 9 This list is expected

to grow, possibly providing new therapeutic targets or allowing an la carte treatment approach. Use of genotype combinations could improve the identification of high-risk groups.87

Mechanisms of organ dysfunction

The pathways leading to organ failures during sepsis can involve upregulation of inflammatory responses and neuroendocrine systems. 70,88,89 Prompt recovery from organ failures in survivors and the normal anatomical appearance of the failed organs suggest that ischaemic and haemorrhagic damage are an uncommon mechanism. Alternatively, mediators such as TNF, interleukin 1_, NO, and oxygen reactive species might inhibit the mitochondrial respiratory chain, inducing cellular dysoxia with reduced energy production, an effect aggravated by hormonal deficiencies.89 Inflammatory mediators might also alter modulation by the autonomic nervous system of biological oscillator functions, 69 leading to disruption of communication between organs, which can precede the development of shock90 and multiorgan dysfunction.91 Lastly, excessive expression of tissue factor, decreased concentrations and activity of coagulation inhibitors (antithrombin III, activated protein C, and tissue factor pathway inhibitor), and insufficient fibrinolytic activity result in a procoagulant state that can interact with inflammatory mediators in a vicious circle, leading to organ failure.92

Diagnosis

Diagnosis of septic shock in patients with systemic inflammatory response syndrome means that the infection must be recognised and proof obtained of a causal link between infection and organ failure and shock (table 3, figure 4). There may be a clinically obvious infection, such as purpura fulminans, cellulitis, toxic shock syndrome, community-acquired pneumonia in a previously healthy individual, or a purulent discharge from a wound or normally sterile cavity (eg, bladder, peritoneal or pleural cavity, or cerebrospinal fluid). Otherwise, diagnosis of infection relies mainly on recovery of pathogens from blood or tissue cultures. However, cultures take 648 h and are negative in 30% of cases; furthermore, sepsis might be related to toxic agents produced by pathogens rather than to the pathogens themselves. Molecular tools such as PCR or microarraybased rapid (<4 h) detection of ten clinically significant bacterial species and of antimicrobial resistance will probably soon supersede conventional cultures. 93 The search for biomarkers of sepsis has been unsuccessful so far, and routine serum assays of endotoxin, procalcitonin, or other markers are not recommended. Indeed, although endotoxaemia is present in 3040% of patients with gram-negative sepsis,94 it can also be detected in gram-positive bacteraemia. Concentrations of procalcitonin in serum are usually increased in sepsis but fail to discriminate between infection and inflammation.95 Nevertheless, the high negative predictive value of low serum procalcitonin (<025 _g/L) could allow discontinuation of unnecessary antibiotics. 96 The triggering receptor

expressed on myeloid cells (TREM-1) is strongly and specifically expressed by neutrophils and macrophages from human tissues infected by bacteria or fungi. 97 Concentrations of soluble TREM-1 in bronchoalveolar lavage fluid of 5 ng/L or more can indicate ventilatorassociated pneumonia,98 and concentrations in plasma of 60 mg/L or more can indicate infection in patients with systemic inflammatory response syndrome.99 Signs of tissue hypoperfusion include areas of mottled skin, oliguria, mental confusion, delayed capillary refill, and hyperlactacidaemia (table 3). However, detection of oliguria entails several hours of observation, and assessment of acute confusion requires knowledge of previous cognitive function. Organ failure scores often ignore pre-existing organ function, mix physiological variables and interventions, use different definitions, and can be useless at the bedside.100 For example, definitions of cardiovascular failure fail to discriminate between cardiac and circulatory dysfunction, although doing so is essential for titration of inotropic drugs and vasopressors. Brain dysfunction is defined according to the Glasgow coma score, which cannot be established in sedated patients. In practice, consensus definitions should be used when availablefor acute lung injury and acute respiratory distress syndrome,101 or for disseminated intravascular coagulation.102 Other organ failures should be considered when introducing supportive therapy to maintain homoeostasis (eg, renal replacement therapy). Recognition of brain dysfunction needs electrophysiological testing to produce data that are independent from the effects of sedation, 103 and cardiac dysfunction is best characterised by echocardiography. 104 Corticosteroid insufficiency should be diagnosed on the basis of a random total cortisol concentration in serum no greater than 415 nmol/L (150 _g/L) or a cortisol increment after corticotrophin no greater than 250 nmol/L (90 _g/L).84,105 When albumin concentrations are 25 g/L or less, the serum free-cortisol cutoff points for defining adrenal insufficiency are 55 nmol/L (20 _g/L) at baseline and 85 nmol/L (31 _g/L) after corticotrophin. 106 However, in everyday practice, unbound plasma cortisol must be derived from the total cortisol and corticosteroidbinding globulin concentrations.107 No evidence lends support to routine screening for other endocrine dysfunctions. Although need for vasopressors to maintain arterial pressure is widely used as the criterion for shock, 1 low central venous oxygen saturation (<70%), 108 direct noninvasive visualisation of altered microcirculation,109,110 or impaired cardiovascular variability90 could provide earlier diagnosis. Establishing a causal link between infection and organ dysfunction is difficult. The likelihood of infection and the presence of another acute illness such as trauma, burns, pancreatitis, cardiac disease, or poisoning should be taken into account (figure 4). A definite diagnosis of septic shock can be made when there is a clinically apparent and microbiologically documented infection and no other acute illness. Septic

shock is likely when clinically apparent infection is present without microbial documentation and without any other acute illness. Septic shock is unlikely when the diagnosis of infection is in doubt, no microbiological documentation is present, and another illness could explain the organ dysfunction. High concentrations of procalcitonin or TREM-1 in tissue can assist in the diagnosis of culture-negative septic shock, and concentrations of procalcitonin in serum lower than 025 _g/L can further rule out infection when septic shock is unlikely.

Treatment

Interventions that can prevent septic shock in some populations include prophylactic antibiotics, 111,112 maintenance of blood glucose concentrations between 4 and 6 mmol/L,113 selective digestive-tract decontamination, 114 strategies for prevention of iatrogenic infections, 115 and immune therapies such as vaccines116,117 and intravenous immunoglobulin (table 4).118,119 Enteral nutritional supplementation, especially with L-arginine, can reduce infection rate after elective surgery and in critically ill patients, but can also increase mortality in such patients.120 The search for vaccines to lipopolysaccharide failed to overcome several hurdles, including identification of target populations and target epitopes for antibodies, as well as rapid generation of antibodies in protective amounts. Patients must be referred promptly to an intensive care unit where management includes careful nursing, immediate control of infection and haemodynamic status, and support to failing organs and to immune, neuroendocrine, and haemostasis responses. After discharge, appropriate rehabilitation and long-term follow-up are mandatory (figure 5). Rapid removal of infected tissues or devices combined with antibiotic treatment is the key to ensuring survival, even though the evidence supporting this approach is merely common sense: indeed, Ambroise Par saved lives by amputating soldiers gangrenous limbs on the battlefield and Fleming did so by discovering penicillin (table 5). Prospective cohort studies showed an increase in mortality of 148 times with inadequate initial antibiotic therapy.121,122 To manage shock and organ dysfunction, fluid resuscitation should be initiated promptly and guided by monitoring of the central venous oxygen saturation, a surrogate of global tissue dysoxia, in addition to clinical signs (table 5).108,123 Fluid challenges can be repeated until cardiac output increases by more than 10% and as long as central venous pressure increases less than 3 mm Hg. Other monitoring tools include right-heart catheterisation, transpulmonary thermodilution techniques, echocardiography, and pulse pressure or vena cava variability,123 and physicians should use the method with which they are familiar. A trial of fluid replacement in 7000 critically ill patients showed no difference in mortality between crystalloids and albumin,124 and an ongoing trial (CRISTAL) is comparing synthetic colloids with crystalloids. For now, crystalloids and synthetic

colloids can be used alone or in combination. Of the vasopressors, dopamine or norepinephrine is recommended as the first-line drug, although phase II trials have yielded conflicting results.123,125 Two large continuing trials in patients with septic shock are comparing epinephrine to combined dobutamine and norepinephrine (CATS) or dopamine to norepinephrine (DeBacker D, personal communication). At present, physicians should use their preferred drug (table 5). When hypotension results mainly from myocardial depression, inotropic agents can be used first. Vasopressors should be titrated to quickly restore systemic mean arterial pressure to 6090 mm Hg, depending on whether the patient had pre-existing hypertension. Secondary endpoints that need monitoring include cardiac performance, tissue dysoxia (eg, lactate), and microcirculation as assessed by capillary refilling time or by sublingual capnography. Optimisation of haemodynamic status could require blood transfusion and, occasionally, vasodilators. 108,109 Patients should be treated with oxygen, and when they have acute lung injury or acute respiratory distress syndrome, with invasive mechanical ventilation with a tidal volume of 67 mL/kg of ideal body weight.126 Daily haemodialysis127 or continuous venovenous haemofiltration with an ultrafiltration rate of 3545 mL/kg per h128 should be used in patients with overt acute renal failure (table 5).88 The first attempts to combat inflammation in patients with septic shock relied on non-selective drugsie, highdose corticosteroids129 and non-steroidal anti-inflammatory drugs.130 These drugs failed to improve survival. Monoclonal antibodies (HA-1A, E5) targeting lipopolysaccharide 131,132 were tested but proved ineffective because of their weak biological activity. 133 By contrast, recombinant bactericidal permeability-increasing protein significantly improved functional outcome in children with severe meningococcal septicaemia (77% of 190 children recovered their preillness level of function compared with 66% of 203 placebo-treated controls, p=0019).134 Other lipopolysaccharide-targeting drugs are being investigated, such as cationic antimicrobial protein 18 (which is also bactericidal), 135 synthetic analogues of lipid A, E5564,136 human lipoproteins which also exert anti-inflammatory effects independently from binding to lipopolysaccharide, 137 and recombinant monoclonal antibody to CD14. 138 Second-generation drugs for septic shock blindly and massively block one factor in the inflammatory cascade, for instance, TNF_, interleukin 1, platelet activating factor, adhesion molecules, arachidonic acid metabolites, oxygen free radicals, bradykinin, phosphodiesterase and C1 esterase, or NO synthase. They failed to improve survival.139 However, because they are biologically active, they might prove beneficial when used in specific strategies. A meta-analysis of 10 sepsis trials (6821 patients) showed an absolute reduction in mortality of 35% with antiTNF drugs.139 Carriers of the TNFB2 allele are at risk for lethal septic shock,9 indicating that antibodies to TNF should be reassessed in this population. Upregulation of inducible NO synthase contributes to hypotension and organ

dysfunction during sepsis.123 However, constitutive NO synthase is essential for homoeostasis, and activity of inducible NO synthase is mainly confined to infected tissues.68 Thus, although non-selective inhibition of NO synthase was associated with increased mortality from septic shock,140 selective inhibition of inducible NO synthase deserves to be investigated. Future therapeutic targets could also include late mediators such as HMGB1 or macrophage migration inhibitory factor, complement C5a and its receptor, or apoptosis (table 6). Polyvalent intravenous immunoglobulins modulate the expression and function of Fc receptors, activation of complement and cytokine networks, production of idiotype antibodies, and activation, differentiation, and effector functions of T and B cells.141 A meta-analysis showed reduced mortality with polyclonal immunoglobulins (n=492; relative risk [RR] 064; 95% CI 051080). However, a sensitivity analysis on highquality trials found no evidence that immunoglobulins were beneficial,142 highlighting the need for adequately powered trials of immunoglobulins in septic shock. Similarly, the clinical benefit from treatment with interferon _ and granulocyte macrophage colony stimulating factor remains uncertain,139 although these drugs might correct a number of immune function variables. 143,144 Recent approaches rely on replacement of hormones or coagulation inhibitors. A meta-analysis129 showed that hydrocortisone in doses from 200300 mg for 5 days or more reduced duration of shock, systemic inflammation, and mortality (RR 080; 95% CI 067095) without causing harm (table 5). Only patients with refractory septic shock and adrenal insufficiency benefit from hydrocortisone, and 50 _g/day oral fludrocortisone can be added.145 A continuing trial (CORTICUS) is investigating the risk to benefit ratio of hydrocortisone in non-refractory septic shock. Vasopressin replacement therapy in doses ranging from 001004 IU/min improved haemodynamics and decreased catecholamine requirements (table 5).146149 However, vasopressin might induce myocardial, cutaneous, or mesenteric vasoconstriction and should not be used until the results of the VAST trial are reported. Recombinant human activated protein C (drotrecogin alfa, 24 _g/kg per h for 96 h) provided a 6% reduction in 28-day mortality from sepsis with at least one recent (<48 h) organ dysfunction.150 A trial of this drug in 11 000 patients with sepsis inducing one organ dysfunction (ADDRESS) was stopped prematurely because of inefficacy. Drotrecogin alfa should be given for septic shock requiring respiratory or renal support, provided there is no risk of bleeding, as detailed in the PROWESS trial (table 5).150 Neither anti-thrombin III151 nor tissue factor pathway inhibitor 54 have proved beneficial in patients with sepsis. Significant interactions were noted between heparin and activated protein C, anti-thrombin III, and tissue factor pathway inhibitor, masking treatment benefits and promoting bleeding. Continuing trials are reassessing these drugs in heparin-free patients. Meanwhile, anti-thrombin III and tissue factor pathway inhibitor should not be used, and heparin should be avoided during infusion of

drotrecogin alfa. Whether heparin is beneficial in patients with sepsis remains unclear.

Outcomes
Mortality

Short-term mortality from septic shock has decreased significantly in recent years. In one study, mortality fell from 62% in the early 1990s to 56% in 2000. 5 Mortality varies from 35% to 70%, depending on factors such as age, sex, ethnic origin, comorbidities, presence of acute lung injury or acute respiratory distress syndrome or renal failure, whether the infection is nosocomial or polymicrobial, and whether a fungus is the causative agent.36 Comparisons with matched patients without sepsis have shown that the mortality attributable to septic shock is 26%.5 Data for long-term mortality in patients with septic shock are scarce. In one retrospective study, the mean lifespan of short-term survivors was reduced from 8 to 4 years.152 A trial including a prospective estimation of one-year survival145 suggested that about 20% of hospital survivors could die within the first year.

Morbidity
In the short-term, septic shock increases the length of stay in the intensive care unit and hospital compared with patients without sepsis,5,6 and results in more organ dysfunction and greater use of the units resources, including right-heart catheterisation, mechanical ventilation, renal replacement therapy, vasopressors, and nurse workload. 5 Septic shock also increases the risk of super-infections6 and neuromuscular complications associated with intensive care.153 Long-term sequels have received less research attention. They might include physical disability related to muscle weakness and post-traumatic stress disorders. Their exact frequency and mechanisms have not been established.

The future

Septic shock remains a major source of short-term and long-term morbidity and mortality, and places a large burden on the healthcare system. The recent identification in people of molecules that sense microbial determinants has been an important step in understanding the molecular and cellular basis of sepsis. Characterisation of the links between inflammation, coagulation, and the immune and neuroendocrine systems have led to international guidelines recommending the use of drotrecogin alfa and low-dose hydrocortisone in the early management of septic shock. New knowledge about apoptosis, leucocyte reprogramming, epithelial dysfunction, and factors involved in sepsis holds promise for the development of new therapeutic approaches. Although improvement of immediate survival is a key goal, physicians are also becoming aware that specific rehabilitation programmes and long-term follow-up are essential.

Search strategy and selection criteria We attempted to identify all relevant studies irrespective of language or publication status (published, unpublished, in

press, and in progress). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004) using the terms sepsis and septic shock, and MEDLINE (1966 to June 2004), EMBASE (1974 to June 2004), and LILACS (www.bireme.br; accessed Aug 1, 2003) databases using the terms septic shock, sepsis, septicaemia, endotoxin, lipopolysaccharide variably combined with incidence, prevalence, cause, origin, diagnosis, management, treatment, therapy, prognosis, morbidity, and mortality. Studies were selected on the basis of relevance to septic shock. Panel: Key dates in sepsis research _ Prognostic discrimination between localised and systemic infections and recognition of fever as a major symptom (Hippocrates, 4th century BCE) _ Description of inflammation: rubor et tumor cum calore et dolore (Celsus, 1st century CE, Galen, 2nd century CE) _ Death of Lucrezia Borgia from puerperal septicaemia (1519) _ Surgery proposed to avoid microbial dissemination from infected wounds (Par, 16th century) _ Antiseptic methods proposed to avoid puerperal septicaemia (Semmelweiss, 1841-47) _ Introduction of the term microbes (Sdillot, 1878) _ Identification of microbes in blood from patients with sepsis (Pasteur, 1879-80) _ Description of phagocytosis as a host response against microbes (Metchnikoff, 1882) _ Role of bacterial toxins described (Roux and Yersin, 1888) _ Concept of endotoxin-induced shock and death (Pfeiffer, 1894) _ Reproduction of infection by auto-inoculation of blood from patients (Moczutkoswky, 1900) _ First antibody to endotoxin (Besredka, 1906) _ Discovery of penicillin (Fleming, 1929) _ First biochemical characterisation of endotoxin (Boivin and Mesrobeanu, 1933) _ Description of stress syndrome (Selye, 1936) _ Dawn of intensive care medicine (Hamburger, Lassen, 1953) _ Description of mechanisms underlying endotoxin shock (Hinshaw, 1956-58) _ Role of tumour necrosis factor _ in endotoxin-induced shock (Beutler and Cerami, 1985) _ Genetic predisposition to infection (Sorensen, 1988) _ Current definitions of sepsis (Bone, 1989) _ First genomic polymorphism associated with severity of sepsis (Stber, 1996)

Septic shock Syok septik, komplikasi yang paling parah sepsis, adalah penyakit mematikan. Dalam beberapa tahun terakhir, telah menarik uang muka dibuat dalam memahami patofisiologi dan pengobatan. Patogen, melalui mereka mikroba terkait pola molekul, memicu peristiwa intraseluler berurutan dalam sel kekebalan, epitel, endotel, dan neuroendokrin sistem. properadangan mediator yang berkontribusi terhadap pemberantasan mikroorganisme yang menyerang dihasilkan, dan mediator anti-inflamasi kendali respons ini. Respon inflamasi menyebabkan kerusakan host jaringan, dan menyebabkan respons anti-inflamasi leukosit pemrograman ulang dan perubahan status kekebalan. Waktu-jendela untuk intervensi pendek, dan pengobatan harus segera mengontrol sumber infeksi dan mengembalikan homoeostasis hemodinamik. Penelitian lebih lanjut diperlukan untuk

membentuk yang cairan dan vasopressors adalah yang terbaik. Beberapa pasien dengan syok septik mungkin mendapat manfaat dari obat-obatan seperti kortikosteroid atau diaktifkan protein C. Lain terapeutik strategi diselidiki, termasuk yang terlambat target mediator properadangan, endotelium, atau neuroendokrin sistem. Pada 1879-1880, Louis Pasteur menunjukkan untuk pertama kalinya bahwa bakteri yang hadir dalam darah dari pasien dengan nifas septicaemia. Seorang wanita selamat, terkemuka Pasteur menyatakan bahwa "Natura medicatrix memenangkan kemenangan", pendapat konsisten dengan gagasan bahwa sepsis adalah respon sistemik untuk melawan patogen (panel, Gambar 1). Namun, konsensus tentang definisi sepsis tercapai hanya satu dekade yang lalu, 1 dan daftar gejala telah diupdate sangat recently.2 Sepsis sekarang didefinisikan sebagai infeksi sistemik dengan bukti peradangan, terdiri dari dua atau lebih dari berikut: meningkat atau menurun suhu atau menghitung leukosit, takikardia, dan bernapas cepat. Septic syok sepsis dengan hipotensi yang berlangsung setelah resusitasi dengan cairan intravena. Biasanya, sistem kekebalan tubuh dan kontrol ketat neuroendokrin proses inflamasi lokal untuk memberantas menyerang patogen. Ketika mekanisme kontrol lokal gagal, terjadi peradangan sistemik, mengubah infeksi untuk sepsis, sepsis berat, atau syok septik. Epidemiologi Kejadian tahunan sepsis adalah 50-95 kasus per 100 000, dan telah meningkat sebesar 9% setiap year.3 ini penyakit account untuk 2% dari penerimaan rumah sakit; kasar 9% dari pasien dengan kemajuan sepsis untuk sepsis berat, dan 3% dari orang-orang dengan pengalaman sepsis berat syok septik, 4 yang menyumbang 10% dari penerimaan untuk perawatan intensif units.5 Puncak terjadinya syok septik dalam keenam dekade life.5 Faktor-faktor yang dapat mempengaruhi orang untuk syok septik termasuk kanker, kekebalan, kronis kegagalan organ, faktor iatrogenik, 3,5,6 dan faktor genetik, 7 seperti sebagai laki-laki, 8 asal etnis non-putih di Utara Amerika, 3 dan polimorfisme dalam gen yang mengatur

immunity.9 Menyebabkan Infeksi pada dada, perut, sistem urogenital, dan menyebabkan aliran darah utama lebih dari 80% kasus dari sepsis.3, Harga 5,6 pneumonia, bakteremia, dan infeksi beberapa-situs telah meningkat terus dari waktu ke waktu, sedangkan infeksi perut tetap infeksi telah berubah dan genitourinari decreased.3, 5 Terjadinya sepsis gram negatif berkurang selama bertahun-tahun 25-30% pada tahun 2000. Grampositive dan infeksi polymicrobial dipertanggungjawabkan 30-50% dan 25% kasus, masing-masing (tabel 1) .3,5,6 The Fakta bahwa bakteri resisten dan jamur sekarang menyebabkan sekitar 25% dari kasus adalah alasan untuk concern.5, 6 Virus dan parasit diidentifikasi dalam 2-4% kasus, tetapi mereka frekuensi bisa underestimated.5 Terakhir, kebudayaan negatif di sekitar 30% kasus, terutama pada pasien dengan masyarakat yang diperoleh sepsis yang diobati dengan antibiotik sebelum masuk. Pathomechanisms Definisi sepsis sering terlalu disederhanakan sebagai hasil tanggapan memperburuk inflamasi. Namun, patogenesis melibatkan beberapa faktor yang berinteraksi dalam rantai panjang peristiwa dari patogen pengakuan untuk besar respon host. Pola dan reseptor Matzinger10 redefinisi kekebalan dengan mendalilkan bahwa aktivitas sistem kekebalan tubuh berasal dari pengakuan dan reaksi terhadap sinyal bahaya internal, daripada dari diskriminasi antara diri sendiri dan nonmolekul. Bahaya sinyal juga termasuk pengakuan eksogen molekul, molekul terkait patogen pola, yaitu molekul permukaan seperti endotoksin (lipopolisakarida), lipoprotein, outermembrane protein, flagellin, fimbriae, peptidoglikan, peptidoglikan terkait lipoprotein, dan lipoteichoic asam, dan motif internal dilepaskan selama lisis bakteri, seperti panas-shock protein dan DNA. Ini molekul yang umum untuk patogen, non-patogenik, dan bakteri komensal, membuat "mikroba terkait

pola molekuler "istilah yang lebih baik. Pola ini diakui oleh reseptor pengenalan pola tertentu, yang menyebabkan ekspresi sitokin. Mikroba ini pola bertindak secara sinergis dengan satu sama lain, dengan host mediator, dan dengan hipoksia. Reseptor pengenalan pola, jumlah korban seperti reseptor dicirikan oleh leucinerich ekstraselular mengulangi pendaftaran dan tol-interleukin-1 sitoplasma reseptor (TIR) domain tersebut saham yang cukup besar homologi dengan reseptor interleukin-1 sitoplasma domain. Saat ini, reseptor tol seperti sepuluh telah dijelaskan pada manusia, dan daftar mereka yang spesifik ligan mikroba adalah growing.11 Sinyal transduksi setelah interaksi antara mikroba terkait molekul pola dan reseptor ini menyebabkan aktivasi banyak adapter, beberapa dengan domain TIR (Protein diferensiasi myeloid [MyD] 88, TIR domaincontaining protein adaptor, TIR reseptor domaincontaining protein adaptor _ menginduksi interferon [TRIF], dan molekul adaptor TRIF terkait), dan kinase protein. MyD88 berinteraksi langsung dengan sebagian besar tol-seperti reseptor dan muncul hulu dari aktivasi transkripsi faktor-_B nuklir. TRIF hasil dalam aktivasi faktor interferon nuklir peraturan faktor 3, mempromosikan produksi interferon _ (gambar 2) 0,11 Selain itu, molekul dalam sitoplasma (MyD88s, interleukin-1 reseptor terkait kinase-M, Tollip, penekan sinyal sitokin 1) atau pada permukaan sel (imunoglobulin tunggal molekul interleukin-1R-terkait, ST2) kontrol negatif kaskade sinyal. protein Nod1 dan Nod2 adalah pola intraseluler pengakuan ligan receptors.12 Nod1 adalah sebuah peptidoglikan fragmen yang hampir eksklusif untuk gram negatif bakteri. Nod2 mendeteksi fragmen tersebut berbeda dan juga mengakui dipeptida muramyl, yang terkecil umum untuk semua peptidoglycans bioaktif fragmen. Empat pengakuan peptidoglikan protein (PGRPs), sepertiga keluarga reseptor pengenalan pola, telah ditandai di rakyat.13 Tiga adalah membran-bound protein, PGRP-I_, PGRP-I_, dan PGRP-L. Keempat adalah molekul larut PGRP-S. Leukosit

Sepsis dikaitkan dengan migrasi diaktifkan leukosit dari aliran darah untuk inflamasi jaringan, 14 dan dengan produksi sumsum tulang diintensifkan leukosit yang dilepaskan ke dalam darah seperti baru dibedakan atau belum menghasilkan sel. Mendalam perubahan muncul dalam perangkat-, darah lymphocytes15 16 dan monosit, 17 serta perubahan dalam penanda permukaan sel (misalnya, kemokin CXC reseptor 2, tumor necrosis factor [TNF] reseptor P50 dan p75, 1R interleukin, C5a reseptor, dan reseptor-tol seperti 2 dan 4). Downregulation ekspresi HLA DR pada monosit tantangan diikuti lipopolisakarida di sehat relawan, 18 dan pada pasien dengan sepsis ditengahi oleh interleukin 1019 dan kortisol, 20 dan berkorelasi dengan death.21 Leukosit melepaskan berbagai protease yang memainkan bagian penting dalam memerangi infeksi. Sebagai contoh, dibandingkan dengan kontrol, tikus yang KO dari gen-elastase neutrofil lebih rentan terhadap sepsis dan kematian setelah intraperitoneal gram-negatif, tetapi tidak gram-positif, infection.22 Pada orang, konsentrasi elastase meningkat dalam plasma dan cairan lavage bronchoalveolar, 23 dan mungkin berkontribusi shock dan disfungsi organ, seperti yang disarankan oleh percobaan menggunakan elastase inhibitor24 atau tikus yang KO dari enzim yang diperlukan untuk protease maturation25 atau protease alami inhibitor26. apoptosis sel pada pasien dengan sepsis bervariasi di sel jenis. Hal ini meningkat untuk darah dan limfosit limpa dan sel dendritik limpa, tidak berubah untuk limpa makrofag dan monosit sirkulasi, dan mengurangi untuk neutrofil darah dan alveolar macrophages.27 Apoptosis juga abnormal di thymic, usus, dan epitel paru dan di otak, tapi tidak dalam endotelium. Pada hewan, glukokortikoid, 28 Fas ligan, 29 dan TNF30 merupakan faktor proapoptotic utama, dan caspase inhibitor atau berlebih dari limfoma B-sel / leukemia-2, mencegah sepsis-induced apoptosis dan death.27 Pada orang, mekanisme dan peran apoptosis dalam patogenesis syok septik masih belum jelas. Ex-vivo percobaan dengan sel darah dari pasien telah menunjukkan tumpul produksi sitokin sebagai respon terhadap mitogens dengan lymphocytes31 penolong (baik-T 1 dan

T pembantu 2 sitokin), 32 dan sebagai respons terhadap lipopolisakarida dengan neutrophils33, 34 dan monocytes.35 Neutrofil dan monosit dari endotoksin-menantang relawan sehat memberikan results.36 serupa, 37 Meskipun interleukin 10 sebagian mungkin bisa menjelaskan sepsis terkait monosit hyporesponsiveness untuk lipopolisakarida, 38 mekanisme molekuler yang mendasari tetap dijelaskan. Sintesis TNF diinduksi oleh lipopolysaccha naik kebutuhan aktivasi dan translokasi nuklir nuklir faktor _B. Dengan demikian, perubahan pada jalur yang faktor ini dapat memberikan kontribusi untuk monosit penonaktifan, sebagai disarankan oleh ex-vivo percobaan dengan lipopolisakarida stimulasi monosit dari pasien, yang upregulation menunjukkan bentuk faktor ini tidak aktif (Homodimer p50p50), dan downregulation dari aktif formulir (heterodimer p65p50) 0,39 Namun, sinyal lain mungkin jalur tetap tidak berubah atau bahkan mengalami stimulasi (misalnya, P38 mitogen protein kinase diaktifkan [MAPK], SP1 aktivasi), sehingga, misalnya, dalam meningkatkan interleukin-10 responses.40 Pada tikus, blokade dari P38 MAPK dicegah sepsis-induced monosit deactivation.41 negatif regulator Banyak dari tol-likereceptorjalur sinyal tergantung tetap diteliti pada sepsis, 42 seperti upregulation cepat interleukin-1 receptor-associated kinase-M di lipopolisakaridadiaktifkan monosit dari patients.43 The istilah anergy, immunodepression, atau immunoparalysis biasanya digunakan untuk menggambarkan status kekebalan kotoran pasien. Namun, sebaliknya dengan sel Menanggapi lipopolisakarida, produksi TNF setelah stimulasi dengan panas-membunuh Staphylococcus aureus, Escherichia coli, atau dipeptida muramyl telah berubah (Data tidak dipublikasikan) leukosit, diversifikasi menyarankan tanggap terhadap mikroba agonists.40 Jadi, kami mengusulkan yang leukosit istilah pemrograman, secara klinis relevansi yang masih harus dieksplorasi. Epitel Pada tikus, bakteri-mediated apoptosis sel epitel bisa berkontribusi untuk pertahanan kekebalan melalui aktivasi Fas di / Fas ligan system.44 Namun, lipopolisakarida mungkin mengubah epitel di persimpangan ketat

paru-paru, hati, dan usus, sehingga meningkatkan bakteri translokasi dan organ failure.45 Nitrat oksida, TNF, _ interferon, dan kotak mobilitas kelompok tinggi 1 (HMGB1) berkontribusi terhadap gangguan fungsional epitel ketat junctions.46 mendasari mekanisme mungkin termasuk diinduksi NO synthase penurunan terkait dalam ekspresi protein occludens ketat zonula persimpangan 1, serta sebagai internalisasi dari kompleks apikal junctional transmembran protein yang disebut adhesi persimpangan molekul 1, occludin, dan claudin-1/4.47 Endotelium sel endotel antara darah dan jaringan mempromosikan pelekatan leukosit, yang kemudian dapat bermigrasi ke dalam jaringan. Di satu sisi, eksperimen dengan KO mice48 atau hewan diperlakukan dengan adhesi moleculespecific antibodies49 menunjukkan bahwa molekul adhesi disajikan pada leukosit atau sel endotel (yaitu, Fungsi limfosit berhubungan antigen 1, interselular molekul adhesi 1, adhesi leukosit endotel molekul 1, L-selektin, dan P-selektin) dapat memberikan kontribusi kerusakan jaringan. Di sisi lain adhesionmolecule, lainnya memburuk blokade jantung dan metabolik functions.50 Pada pasien dengan sepsis, neutrofil menunjukkan peningkatan _4-integrin bergantung dalam kapasitas untuk molekul adhesi vaskuler selular 1 binding.51 Efek terapeutik modulasi adhesi leukosit pada endotelium tetap pada orang yang belum dijelajahi. Endotoksin dan sitokin faktor menyebabkan jaringan ekspresi oleh monosit dan sel endotel di relawan sehat ditantang dengan lipopolysaccharide52 dan pada pasien dengan sepsis.53 Pada hewan, pelindung efek dari administrasi jalur faktor jaringan inhibitor atau antibodi terhadap faktor jaringan atau dari faktor VIIa inhibisi menunjukkan adanya hubungan antara inflamasi dan koagulasi. Pada orang, tidak ada efek perlindungan dari administrasi inhibitor ini telah reported.54 Koagulasi dapat memperburuk peradangan, terutama setelah interaksi antara endotel dengan trombin dan faktor Xa. Dalam model peritonitis, blokade koagulasi yang harmful.55 Namun, dalam heterozigot protein-C-kekurangan tikus, disebarluaskan intravaskuler koagulasi diperparah oleh injeksi

lipopolisakarida, 56 dan, pada orang-orang, pengurangan konsentrasi protein C dikaitkan dengan downregulation dari coagulation.57 Properadangan mediator Selama 15 tahun terakhir bukti, yang meyakinkan bahwa sitokin melindungi terhadap infeksi berasal dari percobaan dengan rekombinan properadangan sitokin terutama TNF-, interleukin 1, dan _-interferon dan antibodi sitokin dan dengan tikus yang KO untuk sitokin tunggal atau reseptornya. pendekatan serupa untuk menyelidiki shock beracun atau infeksi meyakinkan menunjukkan efek mematikan TNF, 1_ interleukin, interleukin 12, interleukin 18, _ interferon, granulocytemacrophage koloni-merangsang faktor, makrofag hambat migrasi faktor, _ interferon, dan HMGB1. Pada orang, sitokin diproduksi dalam kelebihan dan Oleh karena itu terdeteksi dalam darah, di mana mereka biasanya absent.58 Namun, hanya sirkulasi sitokin ujung gunung es, 59 dan sitokin sel-terkait dapat diidentifikasi bahkan ketika jumlah dalam plasma undetectable.35 Sepsis berkaitan dengan peningkatan konsentrasi histamin dalam plasma dari sel mast atau Basofil (atau kedua) setelah aktivasi jalur komplemen dengan upregulation dari anaphylatoxins C3a dan C5a.60 Sedangkan histamin eksogen atau reseptor histamin H2 selektif agonis melindungi terhadap kejutan endotoksin, 61,62 anaphylatoxins meningkatkan permeabilitas pembuluh darah dan halus kontraksi otot, dan chemoattractants untuk leukosit. Selain itu, dibandingkan dengan tikus wildtype, C5tikus kekurangan menanggapi lipopolisakarida dengan mengurangi konsentrasi TNF dan tingkat keparahan yang lebih rendah indeks, dan antibodi untuk C5a atau C5a reseptor dicegah kematian dari sepsis.63 Sebaliknya, tikus dengan knockout sebuah untuk C4, C3, dan reseptor C3 lebih rentan terhadap endotoksin, dan C1 inhibitor dilindungi terhadap kematian dari sepsis.64 Properadangan menginduksi sintesis sitokin fosfolipase A2, cyclo-oxygenase diinduksi, 5-lipoxygenase, dan asetiltransferase, yang berkontribusi sintesis eicosanoids (prostaglandin dan leucotrienes) dan mengaktifkan platelet-faktor. Faktor-faktor ini, bertindak melalui reseptor spesifik G-protein-coupled,

mempromosikan peradangan, mengubah nada vasomotor dan meningkatkan aliran darah dan permeabilitas vaskular. Mencit yang kekurangan dan A2 fosfolipase receptor65 cyclo-oxygenase diinduksi, tapi tidak kekurangan orang-orang dalam 5 lipoxygenase, yang resisten terhadap endotoksin. Namun, prostaglandin E2 juga dapat mengurangi produksi TNF. Superoksida anion, yang dihasilkan oleh NADPH oksidase, oxidises dan mengubah protein dan tak jenuh asam lemak dari fosfolipid. Namun, beberapa dioksidasi fosfolipid dapat mencegah peradangan endotoksin-induced dengan menghalangi interaksi antara lipopolisakarida dan lipopolisakarida-mengikat protein dan CD14.66 Tikus yang telah KO untuk oksidase NADPH senyawa lebih rentan terhadap infeksi berat daripada tikus yang tidak, walaupun mereka sensitivitas terhadap endotoksin tetap unaltered.67 Tikus kekurangan hanya diinduksi NO synthase pameran kurang parah hipotensi setelah endotoksin mematikan challenge.67 Pada orang, sejumlah besar NO yang dirilis setelah terkena endotoksin atau rangsangan sitokin terkait dari aktivitas NO synthase diinduksi di meradang tissues68 dan kapal kelebihan NO walls.69 ini memberikan kontribusi bagi pembangunan kerusakan microvessel, hyporeactivity vaskular, dan disfungsi organ, mungkin dengan induksi dari apoptosis.69 Anti-inflammatory mediator Anti-inflamasi sitokin dan reseptor larut adalah diproduksi dalam jumlah besar selama sepsis. Mereka downregulate produksi sitokin properadangan dan melindungi binatang dari sepsis dan endotoxininduced shock. Efek ini jelas untuk interleukin 10 (walaupun efek dari sitokin ini bervariasi dengan waktu, dosis, dan situs ekspresi), untuk mengubah pertumbuhan faktor _, _ interferon, dan interleukin 4, interleukin 6, dan interleukin 13. Di satu sisi, interleukin 6 menginduksi sejumlah jajaran protein fase akut yang membatasi peradangan, seperti _-1-asam glikoprotein atau Creactive protein. Baru-baru ini, interleukin-1 reseptor antagonis, protein lipopolisakarida mengikat, dan CD14 larut diidentifikasi sebagai protein fase akut. Di sisi lain, interleukin 6 dapat menginduksi depresi miokard selama meningokokus septicaemia.70 Meskipun jumlah besar yang beredar

antagonis interleukin-1 reseptor dan larut reseptor untuk TNF telah dilaporkan pada sepsis, masih belum jelas apakah tingkat ini cukup untuk mengatasi properadangan cytokines.58 Neuromediators memiliki peran penting dalam mengendalikan peradangan (gambar 3). Zat P meningkat sitokin produksi, histamin rilis melalui basophil dan tiang-sel degranulasi, adhesi leukosit dan chemotaxis, dan permeabilitas vaskular. Katekolamin mengganggu sitokin produksi dengan berbagai cara. Norepinefrin, melalui _2-reseptor adrenergik, meningkatkan produksi TNF, 71 sedangkan interaksi epinefrin dengan _2-adrenergik reseptor penurunan produksi seperti di vitro72 dan in vivo dalam lipopolisakarida-menantang relawan sehat, dan juga meningkatkan produksi interleukin 10,73 Selanjutnya, epinefrin meningkatkan produksi interleukin 874 dan menekan produksi NO.75 The antiinflamasi _-efek agonis yang dimediasi melalui mengurangi degradasi I_B_76 dan melalui peningkatan intraselular konsentrasi siklik AMP. Vasoaktif peptida usus dan siklase hipofisis cyclaseactivating peptida dua neuropeptida anti-inflamasi yang menghambat produksi sitokin dan melindungi tikus dari lipopolisakarida lethality.77, 78 Pada tikus diperlakukan dengan lipopolisakarida, stimulasi saraf vagal dilemahkan hipotensi dan penurunan konsentrasi TNF dalam plasma dan liver79 melalui interaksi antara asetilkolin dan subunit _7 dari reseptor nicotinic pada makrofag surface.80 Akhirnya, _-melanocyte merangsang hormon, neuromediator dinyatakan lain di otak, bisa mengurangi peradangan oleh penghambatan properadangan sitokin production.81 Cross-talk antara sitokin dan neurohormones adalah landasan pemulihan homoeostasis selama stress.82 Produksi dan pelepasan vasopresin dan kortikotropin-releasing hormon yang ditingkatkan dengan beredar TNF dan interleukin 1, interleukin 6, interleukin 2, oleh 1_ interleukin disajikan secara lokal dan NO, dan oleh serat aferen vagal. Selain itu, sintesis kortisol dimodulasi oleh interleukin 6 disajikan secara lokal dan TNF_. Upregulated hormon membantu menjaga homoeostasis kardiovaskular dan metabolisme sel, dan membantu fokus dinding-off peradangan. Gangguan

tanggapan endokrin untuk sepsis mungkin timbul dari sitokin, apoptosis neuronal, metabolisme dan iskemik derangements di hipotalamus-hipofisis dan adrenal kelenjar, dan obat administration.83 Kekurangan dalam Kelenjar adrenal function84 dan vasopresin production69 terjadi pada sekitar setengah dan sepertiga dari kasus-kasus syok septik, masing, memberikan kontribusi terhadap hipotensi dan death.84-86 gangguan endokrin lainnya selama sepsis telah jelas mekanisme dan konsekuensi (tabel 2). Polimorfisme genetik Berbagai polimorfisme genetik yang terkait dengan meningkatkan kerentanan terhadap infeksi dan hasil miskin. Penanda kerentanan dapat mencakup tunggal polimorfisme nukleotida gen encoding sitokin (Misalnya, TNF, lymphotoxin-_, interleukin 10, interleukin 18, interleukin-1 antagonis reseptor, interleukin 6, dan interferon _), permukaan sel reseptor (misalnya, CD14, MD2, reseptor tol-seperti 2 dan 4, dan reseptor Fc-gamma II dan III), lipopolisakarida ligan (lipopolisakarida protein mengikat, permeabilitas meningkat bakterisida protein), lektin mannose-mengikat, heat shock protein 70, angiotensin I-converting enzyme, plasminogen aktivator inhibitor, dan 12,9 caspase-daftar ini diharapkan untuk tumbuh, mungkin memberikan target terapeutik baru atau memungkinkan suatu pendekatan la carte pengobatan. Penggunaan kombinasi genotipe dapat meningkatkan identifikasi berisiko tinggi groups.87 Mekanisme disfungsi organ Jalur yang mengarah ke kegagalan organ selama sepsis dapat melibatkan upregulation respon inflamasi dan neuroendokrin systems.70, 88,89 Prompt pemulihan dari kegagalan organ dalam korban yang selamat dan normal tampilan anatomi organ gagal menunjukkan bahwa kerusakan iskemik dan perdarahan merupakan mekanisme biasa. Atau, mediator seperti sebagai TNF, spesies interleukin 1_, NO, dan oksigen reaktif mungkin dapat menghambat rantai pernapasan mitokondria, inducing dysoxia seluler dengan energi berkurang produksi, efek diperburuk oleh hormon deficiencies.89 mediator inflamasi juga mungkin mengubah modulasi oleh sistem saraf otonom osilator fungsi biologis, 69 menyebabkan gangguan

komunikasi antara organ-organ, yang dapat mendahului pengembangan shock90 dan multiorgan dysfunction.91 Terakhir, ekspresi berlebihan faktor jaringan, penurunan konsentrasi dan aktivitas inhibitor koagulasi (Antithrombin III, protein C diaktifkan, dan faktor jaringan jalur inhibitor), dan kurangnya aktivitas fibrinolitik hasil dalam keadaan procoagulant yang dapat berinteraksi dengan mediator inflamasi dalam lingkaran setan, yang mengarah ke organ failure.92 Diagnosa Diagnosis syok septik pada pasien dengan sistemik sindrom respon inflamasi berarti bahwa infeksi harus diakui dan bukti yang diperoleh dari kausal hubungan antara infeksi dan kegagalan organ dan shock (tabel 3, angka 4). Mungkin ada infeksi klinis jelas, seperti purpura fulminans, selulitis, sindrom syok toksik, komunitas-pneumonia di sebelumnya sehat individu, atau debit bernanah dari luka atau biasanya steril rongga (misalnya, kandung kemih, peritoneal atau rongga pleura, atau cairan serebrospinal). Jika tidak, Diagnosis infeksi bergantung terutama pada pemulihan patogen dari darah atau kultur jaringan. Namun, budaya mengambil 6-48 jam dan negatif dalam 30% kasus; lebih lanjut, sepsis mungkin berkaitan dengan bahan beracun diproduksi oleh patogen daripada patogen sendiri. Alat molekul seperti PCR atau microarraybased cepat (<4 h) deteksi bakteri sepuluh spesies klinis signifikan dan resistensi antimikroba akan mungkin segera menggantikan konvensional cultures.93 Pencarian untuk biomarker sepsis telah berhasil sejauh ini, dan tes serum rutin endotoksin, procalcitonin, atau tanda lain tidak direkomendasikan. Memang, meskipun endotoxaemia adalah hadir dalam 30-40% pasien dengan gram-negatif sepsis, 94 juga dapat dideteksi dalam gram-positif bakteremia. Konsentrasi dalam serum procalcitonin biasanya meningkat pada sepsis tetapi gagal untuk membedakan antara infeksi dan inflammation.95 Namun demikian, tinggi nilai prediksi negatif dari serum rendah procalcitonin (<0 25 _g / L) dapat memungkinkan penghentian dari antibiotics.96 yang tidak perlu yang memicu reseptor disajikan pada sel myeloid (Trem-1) adalah kuat dan

secara khusus diungkapkan oleh neutrofil dan makrofag dari jaringan manusia yang terinfeksi oleh bakteri atau fungi.97 Konsentrasi larut Trem-1 di bronchoalveolar lavage cairan dari 5 ng / L atau lebih dapat menunjukkan ventilatorassociated pneumonia, 98 dan konsentrasi dalam plasma 60 mg / L atau lebih dapat menunjukkan infeksi pada pasien dengan respons inflamasi sistemik syndrome.99 Tanda-tanda hypoperfusion jaringan meliputi bidang burik kulit, Oliguria, kebingungan mental, tertunda kapiler isi ulang, dan hyperlactacidaemia (tabel 3). Namun, deteksi Oliguria memerlukan beberapa jam observasi, dan penilaian dari kebingungan akut membutuhkan pengetahuan tentang fungsi kognitif sebelumnya. skor kegagalan organ Organ sering mengabaikan yang sudah ada sebelumnya fungsi, variabel fisiologis campuran dan intervensi, menggunakan definisi yang berbeda, dan dapat berguna pada bedside.100 Sebagai contoh, definisi kardiovaskular kegagalan gagal untuk membedakan antara jantung dan disfungsi peredaran darah, walaupun demikian, ini adalah penting untuk titrasi obat inotropic dan vasopressors. Otak disfungsi didefinisikan menurut koma Glasgow skor, yang tidak dapat dibangun pada pasien diberi obat penenang. Dalam prakteknya, definisi konsensus harus digunakan ketika tersedia untuk cedera paru dan infeksi saluran pernafasan akut distress sindrom, 101 atau untuk disebarluaskan intravaskuler coagulation.102 kegagalan organ lain harus dipertimbangkan ketika memperkenalkan terapi mendukung mempertahankan homoeostasis (misalnya, terapi penggantian ginjal). Pengakuan kebutuhan disfungsi otak electrophysiological pengujian untuk menghasilkan data yang independen dari pengaruh sedasi, 103 dan jantung disfungsi yang terbaik ditandai dengan ekokardiografi. 104 insufisiensi harus Kortikosteroid didiagnosis berdasarkan dari total kortisol acak konsentrasi dalam serum tidak lebih besar dari 415 nmol / L (150 _g / L) atau peningkatan kortisol setelah corticotrophin tidak lebih besar dari 250 nmol / L (90 _g / L) .84,105 Ketika konsentrasi albumin adalah 25 g / L atau kurang, serum cutoff poin kortisol bebas untuk menentukan insufisiensi adrenal adalah 55 nmol / L (20 _g / L) pada awal dan 85 nmol / L (31 _g / L) setelah corticotrophin.106 Namun, dalam

praktek sehari-hari, kortisol plasma harus terikat berasal dari total kortisol dan corticosteroidbinding Tidak ada bukti globulin concentrations.107 meminjamkan dukungan untuk skrining rutin untuk lainnya endokrin disfungsi. Meskipun kebutuhan untuk menjaga arteri vasopressors tekanan secara luas digunakan sebagai kriteria untuk shock, 1 rendah pusat saturasi oksigen vena (<70%), 108 langsung noninvasif visualisasi dari mikrosirkulasi berubah, 109.110 atau variability90 gangguan kardiovaskular bisa menyediakan sebelumnya diagnosis. Membangun hubungan sebab akibat antara infeksi dan disfungsi organ sulit. Kemungkinan infeksi dan adanya penyakit akut lain seperti sebagai trauma, luka bakar, pankreatitis, penyakit jantung, atau keracunan harus diperhitungkan (gambar 4). A diagnosis pasti syok septik dapat dibuat saat ada klinis jelas dan mikrobiologis didokumentasikan dan tidak ada infeksi penyakit akut lainnya. Septic shock mungkin ketika infeksi klinis yang jelas adalah sekarang tanpa dokumentasi mikroba dan tanpa penyakit akut lainnya. Septic shock tidak mungkin saat diagnosis infeksi yang ragu-ragu, tidak ada dokumentasi mikrobiologis hadir, dan lain penyakit bisa menjelaskan disfungsi organ. Tinggi konsentrasi procalcitonin atau Trem-1 dalam jaringan dapat membantu dalam diagnosis shock septik budaya-negatif, dan konsentrasi procalcitonin dalam serum rendah dari 0 25 _g / L lebih lanjut dapat menyingkirkan infeksi saat syok septik tidak mungkin. Pengobatan Intervensi yang dapat mencegah renjatan septik di beberapa populasi meliputi antibiotik profilaksis, pemeliharaan 111.112 konsentrasi glukosa darah antara 4 dan 6 mmol / L, 113-saluran pencernaan selektif dekontaminasi, 114 strategi untuk pencegahan infeksi iatrogenik, 115 dan terapi imun seperti vaccines116, 117 dan intravena imunoglobulin (tabel 4) .118,119 Enteral suplemen gizi, terutama dengan L-arginin, dapat mengurangi tingkat infeksi setelah operasi elektif dan kritis pasien, tetapi juga dapat meningkatkan angka kematian sedemikian patients.120 Pencarian untuk vaksin untuk lipopolisakarida gagal untuk mengatasi beberapa rintangan, termasuk

identifikasi populasi sasaran dan target epitop antibodi, serta generasi cepat antibodi dalam jumlah pelindung. Pasien harus segera dirujuk ke perawatan intensif unit di mana manajemen termasuk keperawatan hati-hati, langsung pengendalian infeksi dan status hemodinamik, dan dukungan untuk gagal organ dan kekebalan tubuh, neuroendokrin, dan haemostasis tanggapan. Setelah debit, rehabilitasi yang tepat dan jangka panjang adalah tindak lanjut wajib (gambar 5). penghapusan cepat jaringan yang terinfeksi atau perangkat gabungan dengan pengobatan antibiotik merupakan kunci untuk menjamin kelangsungan hidup, meskipun bukti yang mendukung pendekatan ini adalah hanya akal sehat: benar, Ambroise Pare menyelamatkan nyawa oleh mengamputasi kaki gangren tentara 'di medan perang dan melakukannya dengan Fleming menemukan penisilin (Tabel 5). penelitian kohort prospektif menunjukkan peningkatan kematian dari 1 4-8 kali dengan antibiotik tidak memadai awal therapy.121, 122 Untuk mengelola shock dan disfungsi organ, cairan resusitasi harus segera dimulai dan dipandu oleh pemantauan saturasi oksigen vena sentral, sebuah pengganti dari dysoxia jaringan global, di samping klinis tanda-tanda (tabel 5) .108,123 tantangan Fluida dapat diulang sampai output jantung meningkat dengan lebih dari 10% dan selama meningkatkan tekanan vena sentral kurang dari 3 mm Hg. alat monitor lainnya termasuk kateterisasi jantung kanan, transpulmonary thermodilution teknik, Ekokardiografi, dan pulsa tekanan atau vena kava variabilitas, 123 dan dokter harus menggunakan metode ini dengan yang mereka kenal. Sebuah pengadilan pengganti cairan dalam 7.000 pasien sakit kritis tidak menunjukkan perbedaan kematian antara kristaloid dan albumin, 124 dan percobaan berlangsung (Cristal) adalah membandingkan koloid sintetik dengan kristaloid. Untuk saat ini, kristaloid dan sintetik koloid dapat digunakan sendiri atau dalam kombinasi. Dari vasopressors, dopamin atau norepinefrin adalah direkomendasikan sebagai obat lini pertama, meskipun tahap II persidangan telah menghasilkan results.123 bertentangan, 125 Dua besar melanjutkan persidangan pada pasien dengan syok septik adalah

membandingkan epinefrin untuk dobutamine gabungan dan norepinefrin (CATS) atau dopamin untuk norepinefrin (DeBacker D, komunikasi pribadi). Saat ini, dokter harus menggunakan obat yang mereka sukai (Tabel 5). Bila hipotensi terutama hasil dari miokard depresi, agen inotropic dapat digunakan pertama. Vasopressors harus dititrasi untuk segera memulihkan tekanan arteri sistemik bermaksud 60-90 mm Hg, tergantung pada apakah pasien itu sudah ada sebelumnya hipertensi. Sekunder endpoints yang perlu pemantauan termasuk kinerja jantung, dysoxia jaringan (misalnya, laktat), dan mikro yang dinilai oleh kapiler mengisi ulang waktu atau oleh capnography sublingual. Optimasi dari status hemodinamik dapat memerlukan transfusi darah dan, kadang-kadang, vasodilators.108, 109 Pasien harus diperlakukan dengan oksigen, dan ketika mereka telah cedera paru-paru akut atau sindrom gangguan pernapasan akut, dengan invasif