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The role of the gut in sepsis
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The role of the gut in sepsis
situations, but none of the signs are specific enough to be pathognomonic on their own. A high degree of suspicion is required and the possibility of sepsis should be entertained when these signs are present.
Marcel Gatt
Abstract
Pathophysiology of sepsis
Sepsis is defined as the systemic inflammatory response syndrome (SIRS) associated with suspected or confirmed infection. As such, it is implicit that two components are necessary in the causation of surgical sepsis: a source of infection as well as a SIRS response by the patient. In recent years, the management of patients with sepsis has been aided by a much better understanding of the underlying pathophysiological processes which occur. In particular, we have a better perception of the complex interactions between the host and the invading organisms as well as a better appreciation of the cellular and extracellular pathways involved, including, but not confined to the complexly intertwined roles of the immunological system, the complement cascade and the coagulation pathway, as well as the role of the gut in driving this process. Given the plethora of homeostatic functions of the gastrointestinal tract, it is self evident, albeit somewhat poorly represented in the medical literature, that this organ plays a central role in the process. This article reviews the role played by the gut in the development of sepsis with a particular emphasis on the surgical patient. The passage of viable bacteria or its components across the gut barrier in a process known as bacterial translocation as well as other mechanisms are also discussed.
Homeostasis is maintained in vivo by a complex interplay of a number of mechanisms aimed at maintaining the status quo of the internal milieu. Such mechanisms include the immune system (with both its innate and adaptive components), as well as the complement and coagulation cascades. With respect to the immune system, a tightly maintained balance between opposing yet complimentary pro-inflammatory and anti-inflammatory mediators maintains health and homeostasis. Any upset in this tightly controlled balance may result in disease. The clinical manifestations of sepsis result from the complex interactions between the immune and other systems of the host and the infecting microorganisms. Cells of the host’s innate immune system recognize microorganisms and initiate responses to these microbes or their products. This response is mediated through a number of host cell surface receptors and proteins and a battery of microbe antigens. Host cell surface receptors include the so-called pattern recognition receptors (PRRs) and toll-like receptors (TLRs). These are expressed by cells of the innate immune system, which in turn employs a limited number of germline-encoded PRRs that recognize invariant pathogen-associated microbe antigens including small molecular motifs conserved within different classes of microbes known as pathogenassociated molecular patterns (PAMPs). Better known examples of PAMPs include lipopolysaccharides (LPS, endotoxins) expressed by virulent Gram-negative bacteria, peptidoglycan, lipopeptides, lipoteichoic acid (a component of gram-positive bacterial cell walls), flagellin and bacterial DNA. While it is beyond our scope to review the complexities of the immune system and other homeostatic pathways, it should suffice to say that activation of a variety of complex metabolic systems, including the immune and coagulation cascade pathways result from hosteantigen interaction, culminating in what is recognized as the septic response. With the involvement of such complex pathways and with the contribution of so many intermediate substances, one may be forgiven to think that the level of one or more of these intermediaries may be used to diagnose sepsis with some certainty or accurately monitor its progress. In the last few decades more than 170 biomarkers have been studied both as diagnostic markers as well as prognostic indicators for sepsis, but none of them have been found to have sufficient sensitivity or specificity on their own to be used routinely in clinical practice. CRP and procalcitonin (PCT) have been used most widely, but they both have their limitations when used to distinguish sepsis from other inflammatory conditions as well as when they are used as prognostic indices. In moderate to severe sepsis the inflammatory response causes an imbalance of procoagulants and anticoagulants, which culminates in disseminated intravascular coagulation (DIC). The formation of clots eventually cause thrombosis of small vessels and impaired tissue perfusion. The higher levels of cytokines and the secondary mediators in severe sepsis lead to hypotension due
Keywords Critically ill; gut failure; gut function; intestinal failure; mortality; multi-organ failure; multiple organ dysfunction syndrome; nutrition; sepsis; surgery; systemic inflammatory response syndrome
Introduction The word ‘sepsis’ is derived from Greek and means to decay or to make rotten. In modern practice, the phrase sepsis has come to represent a catch-all term referring to the changes observed when living organisms are subjected to an insult of an infectious nature. There have been many attempts to define sepsis more systematically1,2 and this has introduced a dizzying array of seemingly synonymous albeit novel and distinct concepts. Terms such as the systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) carry specific meanings and are often a source of confusion. For purposes of clarity, these and other relevant terms are summarized in Table 1. Despite numerous advances in clinical care, sepsis is widely recognized as a primary cause of morbidity and mortality in hospitalized patients. This is particularly true in the critically ill and the surgical patient. The diagnosis of infection and underlying sepsis in such patients can be complex, and the challenge is often intensified by multiple coexisting disease processes. The signs of sepsis suggested by the Sepsis Conference of 2001 and summarized in Table 2 are a useful guide to diagnosis in such
Marcel Gatt MD FRCS is a Consultant General and Colorectal Surgeon at the Combined Gastroenterology Research Unit, Scarborough General Hospital, York Teaching Hospitals NHS Foundation Trust, Scarborough, UK. Conflicts of interest: none declared.
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Definitions (adapted from3,4) Infection
Systemic inflammatory response syndrome (SIRS)
Sepsis Severe sepsis Septic shock
Multiple organ dysfunction syndrome (MODS)
A pathologic process caused by suspected or proven invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms or a clinical syndrome associated with a high probability of infection Presence of at least two or more of the following, one of which must be abnormal temperature or white blood cell (WBC) count in children: C Core temperature >38.3 C, >38.5 C in children, or <36 C C Heart rate >90 beats/minute or in children a mean heart rate >2 standard deviations (SD) above normal for age, or in children <1 year of age bradycardia defined as a mean heart rate <10th percentile for age C Respiratory rate >20 breaths/minute or PaCO2 <32 mmHg, or in children >2 SD above normal for age; or need for mechanical ventilation C WBC count >12,000/mm3 or <4000/mm3, or >10% immature (band) forms, or in children elevated or depressed level for age Systemic inflammatory response syndrome associated with suspected or confirmed infection, positive blood cultures are not necessary Sepsis complicated by cardiovascular organ dysfunction or acute respiratory distress syndrome or dysfunction of two or more other organs Cardiovascular collapse related to severe sepsis despite adequate fluid resuscitation characterized by hypotension defined as systolic blood pressure (SBP) <90 mmHg (in children a pressure <2 SD below normal for age), mean arterial pressure (MAP) <60 mmHg or a reduction of >40 mmHg on baseline SBP The presence of altered organ function in a patient who is acutely ill and homeostasis cannot be maintained without intervention. The criteria are: C Hypoxaemia (PaO2/FiO2 <300) C Acute oliguria (urine output <0.5 ml/kg/hour for 2 hours) or creatinine >2.0 mg/dl C Coagulopathy (platelet count <100,000, international normalized ratio >1.5 or partial thromboplastin time >60 seconds C Ileus C Plasma bilirubin >4 mg/dl
Table 1
to systemic vasodilation, diminished myocardial contractility, and systemic leucocyte adhesion due to widespread endothelial damage and activation as well as diffuse alveolar capillary damage in the lung. MODS ensues from these combined effects, most notably affecting the liver, kidneys and the central nervous system. In this situation, the patient can succumb rapidly unless the underlying infection (and the resulting LPS overload) is brought under control.2 It is increasingly recognized that the gut plays a pivotal role in both the initiation as well as the propagation of this septic response.
Typically, the numbers are lower in the stomach due to the hostile environment here. A low pH and slow transit promote the killing of ingested microbes. Ordinarily the proximal small bowel has fewer microbes than the distal small bowel and the number of microorganisms gets exponentially higher distal to the ileocaecal valve. The gut also serves as a barrier against luminal microbes and other antigens, essential in separating self from non-self; the so-called ‘intestinal barrier function’ of the gut. This barrier role of the gut is highly effective. The fact that luminal contents in the caecum have a bacterial concentration of the order of 1012 organisms/ml of faeces, whilst portal blood, mesenteric lymph nodes (MLN) and indeed tissues one cell deep to the intact intestinal mucosa are usually sterile, dramatically illustrates the efficacy of this barrier. Anaerobes are the predominant flora in the GI tract, outnumbering aerobes by approximately two orders of magnitude. The adherence of the resident gut microflora to endothelial cells, mucus and to each other creates a highly anaerobic environment which helps to prevent adherence, proliferation, overgrowth and invasion of pathogens. This phenomenon associated with the physical barrier is termed ‘colonization resistance’.5 The barrier role of the gut serves to manage luminal antigens, encouraging the symbiotic relationship between man and enteric bacteria without which humans could not survive, while ensuring that the internal milieu remains sterile. Breakdown or
Sepsis and the gut It is well established that the primary function of the gastrointestinal (GI) tract is that of nutrition, being involved in the digestion and absorption of nutrients, fluids and trace elements from the diet. The gut, however, is a highly complex organ and it satisfies a plethora of additional functions. Amongst other roles, it is also involved in the production of numerous hormones with both local and systemic effects, and participates in the excretion of waste by-products of metabolism. Its gut-associated lymphoid tissue (GALT) is the single largest immunological organ and cytokine producer in the body. The normal GI tract harbours large numbers of both aerobic and anaerobic bacteria which exist in symbiosis with man.
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The idea of bacterial translocation is not new. The notion that the alimentary tract, teeming with its own bacterial flora, could represent a source of sepsis under certain conditions has intrigued clinicians for many years. In 1891 and 1895, two separate investigators hypothesized that viable bacteria could pass through the intact gut wall in vivo. It was Berg and Garlington who in 1979 defined this phenomenon as ‘bacterial translocation’. Nowadays, bacterial translocation is used to describe the passage of viable resident bacteria from the gastrointestinal tract, across the gut mucosa, to normally sterile tissues such as the MLN and other internal organs. The term also applies to the passage of inert particles and other antigenic macromolecules, such as lipopolysaccharides (LPS), endotoxins and peptidoglycans, across the intestinal mucosal barrier.6 In this respect, the gut can be considered both as a target organ for pathogens as well as a source of pathogenic organisms. This role of the gut as the so called ‘undrained abscess’ or ‘motor’ of multiple organ failure has been used to explain the absence of a discreet focus of infection in most patients with delayed SIRS and MODS, particularly prevalent in those with prolonged critical illness. Numerous modifications to the ‘gut origin of sepsis hypothesis’ have been put forward to attempt to define this process of gut-derived sepsis. Deitch proposed the ‘multi-hit model’7,8 wherein an initial insult results in splanchnic hypoperfusion (first hit) with the gut becoming a major site of pro-inflammatory factor production. Resuscitation results in reperfusion which leads to an ischaemia-reperfusion injury to the intestine (second hit) with a resultant loss of gut barrier function and an ensuing enhanced gut inflammatory response, without the need for translocation of microbes as far as the MLN or beyond. Once bacteria or endotoxin cross the mucosal barrier, they can trigger an augmented immune response such that the gut becomes a pro-inflammatory organ, releasing chemokines, cytokines and other pro-inflammatory intermediates which affect both the local as well as the systemic immune systems (third hit), finally resulting in SIRS and MODS. Another modification of the ‘gut origin of sepsis hypothesis’ is known as the ‘gut-lymph theory’9,10 which proposes that macrophages and other immune cells in the submucosal lymphatics of the gut wall or the MLN trap the majority of translocating bacteria. However, those that survive, or the cell wall and protein components of the dead bacteria (including lipopolysaccharides and peptidoglycans) along with the cytokines and chemokines generated in the gut, travel via the mesenteric lymphatics to the cysterna chyli, and via the thoracic duct empty into the left subclavian vein to reach the right side of the heart. These inflammatory products then enter the pulmonary circulation and activate the alveolar macrophages. In so doing, they contribute to acute lung injury and the progression to acute respiratory distress syndrome (ARDS) and MODS. If nothing else, the number of existing theories is testament to the fact that the underlying mechanisms involved are poorly understood. Indeed, whist it is tempting to think that any bacteria or endotoxin passing through the intestinal barrier might cause septic complications in the host, there is growing evidence to the contrary and that translocation may in fact be a normal ubiquitous phenomenon. It is possible that translocation occurs to allow the alimentary tract to be exposed to and sample antigens within the lumen such that the gut can mount a controlled local
Signs of sepsis (adapted from3) General signs and symptoms
C C C C C
Generalized haematological/inflammatory reaction
C
Haemodynamic alterations
C
C
C C
C C C
Signs of organ dysfunction
C C C
C C C
C
Rigours Fever or hypothermia Tachypnoea/respiratory alkalosis Positive fluid balance Oedema Increased or decreased WBC count Increased inflammatory markers (CRP, PCT, IL-6) Arterial hypotension, Unexplained tachycardia Increased cardiac output/low systemic vascular resistance/high SvO2 Altered skin perfusion Decreased urine output Unexplained hyperlactaemia/increased base deficit Hypoxaemia (acute lung injury) Altered mental status Unexplained alteration in renal function Hyperglycaemia Thrombocytopenia/DIC Unexplained alteration in liver function tests Intolerance to feeding
CRP, C-reactive protein; DIC, disseminated intravascular coagulation; IL-6, interleukin-6; PCT, procalcitonin; SvO2, mixed venous oxygen saturation; WBC, white blood cell.
Table 2
overwhelming of this barrier may result in the ingress of viable bacteria and their antigens with the development of sepsis, initiation of a cytokine-mediated SIRS, MODS, and death. In summary, the gut has many functions that are essential to maintaining homeostasis, without which survival would be, at best, difficult, if not impossible. Because of these numerous homeostatic functions, it is increasingly recognized that the gut plays a pivotal role in the development and propagation of sepsis. In particular, breakdown or overwhelming of gut barrier function may result in the ingress of viable bacteria and their antigens with the development of sepsis, initiation of a cytokinemediated SIRS, MODS, and eventually death. This process whereby bacteria or their products breach the gut barrier is known as ‘bacterial translocation’ and describes the so called ‘gut origin of sepsis hypothesis’.
The gut barrier, bacterial translocation, oral tolerance and gut dysfunction Theories relating to the initiation and propagation of sepsis by the gut abound. The most widely accepted mechanism centres around the translocation of bacteria and/or their products from the lumen of the gut into the internal milieu.
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do not induce bacterial translocation. Alterations in mucosal architecture or intestinal permeability may indicate certain changes in intestinal barrier function but do not necessarily equate with alterations in the prevalence of bacterial translocation or sepsis. As such, the nature of the nutritional support that should be provided to patients should be determined by their tolerance to EN and not by unfounded fears regarding TPN or unjustified assumptions concerning the role of gut barrier function.12 In this respect, if TPN is necessary it should not be withheld on the wrong assumption that it will promote bacterial translocation. It is self evident, however, that maintaining patients on EN requires a functioning gut. As such, one true advantage of EN over TPN, other than cost, lies in the fact that tolerance to EN can be used to assess underlying gut function. There is also some evidence that EN may decrease the prevalence of stress ulceration, but clearly whether this is a direct result of EN administration, or simply because EN is only possible in a wellfunctioning gut (whose repair and barrier mechanisms are intact), remains somewhat controversial. As a functioning gastrointestinal tract remains an essential prerequisite for maintaining the integrity of the immune system and gut barrier function, and this has a direct effect on sepsis, it remains logical to institute EN whenever possible, but without withholding TPN when this becomes necessary. Gut hypoperfusion and subsequent reperfusion injury are thought to represent important early sources of pro-inflammatory mediators. Both events trigger activation of stress sensitive protein kinases that converge on transcription factors, which regulate the expression of pro-inflammatory genes. Pro-inflammatory mediators and cytokines generated in the gut reach the circulation via intestinal lymphatics. Even when the bacteria or bacterial products are trapped in the gastrointestinal wall or intestinal lymph nodes not reaching the systemic circulation, they increase the inflammatory response of the gut. Studies in animal models have shown a complex interplay within the gastrointestinal wall between mast cells, macrophages and glial cells on one hand, and neurons and smooth muscle cells on the other, involving intracellular signalling pathways, cytokines, mediators in afferent neuronal signalling and anti-inflammatory vagal pathway. As these mechanisms are being elucidated further, they have also led to increased interests in research on antiinflammatory and prokinetic drugs in preventative strategy against multi-organ failure.13 In view of the methodological problems in confirming bacterial translocation as a measure of gut barrier function, in vivo investigations in humans have had to be restricted to patients undergoing laparotomy during which MLN can be sampled. As such there is only limited data available relating to specific interventions which might preserve intestinal barrier function or limit bacterial translocation. Based on the best currently available knowledge, glutamine supplementation, aggressive and targeted nutritional intervention, maintaining good splanchnic flow whilst limiting other inotropic support, the judicious use of antibiotics and directed selective gut decontamination regimes, amongst other interventions hold some promise of attenuating gut failure or enhancing the return of gut function.12 In so doing, they may limit bacterial translocation, as an epiphenomenon associated with gut barrier dysfunction. Whether these and other
immune response helping to keep these antigens away from the internal milieu, a process known as ‘oral tolerance’. It is then only when the host’s immune defences are overwhelmed, attenuated or otherwise defective that septic complications arise. This failure of the gut barrier is one of the manifestations of gut dysfunction, and in this setting bacterial translocation represents little more than an epiphenomenon of gut barrier dysfunction. In humans, the most reliable method of assessing bacterial translocation is by culture of MLN. This involves the limited sampling of MLNs at the time of laparotomy using aseptic techniques, and their subsequent culture. A positive culture is considered to indicate bacterial translocation. It is important to emphasize that, given the obvious limitations pertaining to MLN harvest and subsequent culture, the literature is full of studies using surrogate measures of intestinal barrier function. These include blood cultures with concomitant faecal cultures, intestinal immune markers, bowel scrapings, intestinal permeability measurements, the culture of nasogastric aspirates, assessment of villous height and many others. It is felt that these do not represent good surrogates of bacterial translocation nor of intestinal barrier function, and as such the findings of such studies should be interpreted with great caution. Implicit to the many homeostatic roles of the gastrointestinal tract is the recognition that gut dysfunction (such as occurs in the setting of ileus for example) or gut failure will result in poorer patient outcomes.11 As gut dysfunction and failure is closely linked with the need for total parenteral nutrition (TPN), many have made the error of associating poorer outcomes (especially septic complications) which are sometimes recorded in patients receiving TPN with the administration of TPN itself. This has resulted in misconstrued avoidance of TPN especially in critically ill patients most at risk of both malnutrition and net nitrogen loss, hence arguably those patients which need adjuvant nutritional support the most. Fortunately, this misplaced concern that TPN may increase sepsis is recognized and is being readdressed. Today there is increased recognition that higher levels of sepsis previously noted in patients receiving TPN related to other factors. These included hyperglycaemia from erroneous overfeeding and also the recognition that gut failure (and subsequently failure of gut barrier function) itself predisposed to both the higher levels of sepsis as well as the subsequent need for TPN. In this respect, TPN is an innocent confounding factor of sepsis.12 It is widely recognized that early institution of nutritional support is of benefit, particularly in patients with severe infirmity. Not surprisingly, most reviewers of nutritional support therapy urge the use of enteral nutrition (EN) as opposed to TPN given the aforementioned (and other) falsely held concerns about TPN. It is often believed that TPN results in mucosal atrophy, increased intestinal permeability, and other deleterious effects on the gut and reflect damage to the intestinal barrier. Similarly, it is often reported that luminal nutrients during EN have the opposite effect. There is no evidence to suggest that in humans bacterial translocation is reduced by the use of EN, that short-term (21 days) TPN is associated with villus atrophy or significant changes in intestinal permeability or indeed that alterations in intestinal permeability will, in turn, predispose to an increased prevalence of bacterial translocation or sepsis.12 Starvation, malnutrition, or the absence of luminal nutrients by themselves
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gut-directed interventions will decrease sepsis or attenuate the SIRS response remains to be seen. Future potential in preserving intestinal barrier function may lie in targeted immunomodulation of the gut-associated lymphoid tissue as well as other gutdirected therapies aimed at attenuating gut failure. The fact remains that the gut is increasingly recognized as having a pivotal role in the onset and propagation of sepsis, albeit underrepresented in published medical literature. Testament to this underrepresentation is the absence of gut-related parameters from most, if not all, clinical outcome scoring systems (e.g. APACHE, POSSUM, SOFA), with barely a mention in the most recent issue of the ’surviving sepsis campaign’ (SCC).14 Many of the mechanisms involved remain poorly appreciated, and a better understanding in this respect may help delay or prevent the onset of SIRS and MODS, ultimately improving outcomes especially in critically ill and surgical patients.
Initial resuscitation and infection issues (adapted from14) Initial resuscitation C Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion. C Goals during the first 6 hours of resuscitation: central venous pressure 8e12 mm Hg mean arterial pressure (MAP) 65 mm Hg urine output 0.5 mL/kg/hour central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively. C
Screening for sepsis and performance improvement C Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy. C Hospitalebased performance improvement efforts in severe sepsis.
The ‘surviving sepsis campaign’ (SSC) and the management of sepsis The SSC is an international effort by a group of experts in the field aimed at increasing awareness of and improving outcomes in severe sepsis. In 2004 the group published the first internationally accepted guidelines that clinician could use by the bedside to improve outcomes in patients with severe sepsis and septic shock. In 2008 an updated guideline was published using a new evidence based methodology for assessing the quality of evidence and the strength of recommendations based on this evidence.15 The latest version of these guidelines has only recently been published in 2013 following a consensus conference in 2012.14 In essence, the SCC recommends the use of a number of ‘care bundles’ intended on improving outcomes in septic patients. It must be emphasized that the recommendations from these guidelines cannot replace the decision-making ability of the clinicians when faced with an individual patient’s unique set of clinical variables both on the intensive care unit (ICU) and nonICU settings.15 There are many critics of the SSC recommendations who find the grouped therapies or ‘care bundles’ for particular subset of patients to be somewhat didactic and often lacking in evidence. Nonetheless, there is some evidence that the process of care and outcomes have improved after educational programmes were instituted based on the various incarnations of the SSC and its care bundles.16 However, the persistent lack of emphasis on the pivotal role played by the gut, and tailored therapies to target gut dysfunction remains a concern. The clinical recommendations in order to achieve a significant (estimated at approximately 25%) reduction in mortality from severe sepsis are summarized in Boxes 1 to 3 and are adapted directly from the SCC.14 These include care bundles aimed at the initial resuscitation phase, which should also include source control of infection, and administration of antibiotics. The recognition that haemodynamic support to include the appropriate use of directed fluid therapy, vasopressor and inotropic agents, as well as steroids is similarly essential. Finally, other supportive therapies such as the targeted use of blood and blood products, specific mechanical ventilation in sepsis, the use of analgesics and sedation, glycaemic control, renal replacement therapy, nutritional support and the use of deep venous
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In patients with elevated lactate levels, target resuscitation to normalize lactate.
Diagnosis C Cultures as clinically appropriate before antimicrobial therapy if no significant delay (>45 minutes) in the start of antimicrobial(s). C At least two sets of blood cultures (both aerobic and anaerobic bottles) to be obtained before antimicrobial therapy. C Ensure invasive candidiasis is included in the differential diagnosis of cause of infection. C Imaging studies performed promptly to confirm a potential source of infection. Antimicrobial therapy C Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis. C Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis. C Antimicrobial regimen should be reassessed daily for potential de-escalation. C Discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection. C Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multi drug resistant bacterial pathogens. C Empiric combination therapy should not be administered for more than 3e5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. C Duration of therapy typically 7e10 days; longer courses may be appropriate in some patients. C Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin.
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C
Vasopressors C Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg. C Norepinephrine as the first choice vasopressor. C Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. C Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage. C Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03e0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents). C Dopamine as an alternative vasopressor agent to norepinephrine to be used only in highly selected patients (e.g. patients with low risk of tachyarrhythmias and absolute or relative bradycardia). C Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. C Low-dose dopamine should not be used for renal protection. C All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.
Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause.
Source control C A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hours after the diagnosis is made, if feasible. C When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (e.g. percutaneous rather than surgical drainage of an abscess). C If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established. Infection prevention C Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia. C Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilatorassociated pneumonia in ICU patients with severe sepsis.
Box 1
Inotropic therapy C A trial of dobutamine infusion up to 20 micrograms/kg/min should be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. C Do not use a strategy to increase cardiac index to predetermined supranormal levels.
Haemodynamic support and Adjunctive Therapy recommendations (adapted from14) Fluid therapy of severe sepsis C Use crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. C Do not use hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. C Use albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. C Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolaemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. C A fluid challenge technique should be applied wherein fluid administration is continued as long as there is haemodynamic improvement either based on dynamic (e.g. change in pulse pressure, stroke volume variation) or static (e.g. arterial pressure, heart rate) variables.
Corticosteroids C Do not use intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore haemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, suggest intravenous hydrocortisone alone at a dose of 200 mg per day. C Do not use the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. C Taper hydrocortisone in treated patients when vasopressors are no longer required. C Do not administer corticosteroids for the treatment of sepsis in the absence of shock. C When hydrocortisone is given, use continuous flow.
Box 2
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Other Supportive Therapy of Severe Sepsis recommendations (adapted from14) C
Blood product administration C Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, (such as myocardial ischaemia), red blood cell transfusion should occur only when haemoglobin concentration decreases to <7.0 g/dL to target a haemoglobin concentration of 7.0e9.0 g/dL in adults. C Do not use erythropoietin as a specific treatment of anaemia associated with severe sepsis. C Fresh frozen plasma should not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. C In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 109/L) in the absence of apparent bleeding.
Glucose control C Employ a protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose 180 mg/dL rather than an upper target blood glucose 110 mg/dL. C Monitor blood glucose values every 1e2 hours until glucose values and insulin infusion rates are stable and then every 4 hours thereafter. C Interpreted glucose levels obtained with point-of-care testing of capillary blood with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values.
Immunoglobulins C Do not routinely use intravenous immunoglobulins in adult patients with severe sepsis or septic shock.
Renal replacement therapy C Continuous renal replacement therapies and intermittent haemodialysis are equivalent in patients with severe sepsis and acute renal failure. C Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients.
Selenium C Do not use intravenous selenium for the treatment of severe sepsis. Mechanical ventilation of sepsis-Induced acute respiratory distress syndrome (ARDS) C Target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS. C Plateau pressures should be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung should be 30 cm H2O. C Positive end-expiratory pressure (PEEP) should be applied to avoid alveolar collapse at end expiration. C Prone positioning should be used in sepsis-induced ARDS patients with a PaO2/FiO2 ratio 100 mm Hg in facilities that have experience with such practices. C Mechanically ventilated sepsis patients should be maintained with the head of the bed elevated to 30e45 degrees to limit aspiration risk. C A weaning protocol should be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy set criteria. C Avoid the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS. C Employ a conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion.
Bicarbonate therapy C Do not use sodium bicarbonate therapy for the purpose of improving haemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidaemia with pH 7.15. Deep vein thrombosis prophylaxis C Prescribe patients with severe sepsis daily pharmacoprophylaxis against venous thromboembolism (VTE). This should be accomplished with daily subcutaneous lowmolecular weight heparin (LMWH). If creatinine clearance is <30 mL/minute, use dalteparin or another form of LMWH that has a low degree of renal metabolism or UFH. C Treated patients with severe sepsis with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible. C Septic patients who have a contraindication for heparin use (e.g. thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral haemorrhage) should not receive pharmacoprophylaxis, but receive mechanical prophylactic treatment, such as graduated compression stockings or intermittent compression devices, unless contraindicated. When the risk decreases start pharmacoprophylaxis. Stress ulcer prophylaxis C Prescribe stress ulcer prophylaxis using H2 blocker or proton pump inhibitor to patients with severe sepsis/septic shock who have bleeding risk factors. C When stress ulcer prophylaxis is used, use proton pump inhibitors rather than H2RA. C Patients without risk factors do not require prophylaxis.
Sedation, analgesia, and neuromuscular blockade in sepsis C Minimize the use of continuous or intermittent sedation in mechanically ventilated sepsis patients, targeting specific titration endpoints. C Avoid neuromuscular blocking agents (NMBAs) if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs
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must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used. Employ a short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a PaO2/FiO2 <150 mm Hg.
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in the initiation and propagation of some episodes of sepsis, much still remains to be understood in the expectation that effective therapies can be developed to improve the survival from sepsis. There remains much scope for research in this field aimed primarily at a better understanding of the mechanisms involved in causing surgical sepsis, and developing ways to prevent it. A
Nutrition C Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock. C Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (e.g. up to 500 calories per day), advancing only as tolerated. C Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock. C Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis.
REFERENCES 1 Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Med 2002; 28: 824e33. 2 Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765e77. 3 Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 2003; 29: 530e8. 4 Goldstein B, Giroir B, Randolph A. International paediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in paediatrics. Pediatr Crit Care Med 2005; 6. 5 Dunn DL. Autochthonous microflora of the gastrointestinal tract. Perspect Colon Rectal Surg 1990; 2: 105e19. 6 Gatt M, Macfie J. Bacterial translocation in surgical patients. In: . Recent advances in surgery, vol. 28. London: The Royal Society of Medicine Press Limited, 2005; 23e32. 7 Deitch EA. Bacterial translocation or lymphatic drainage of toxic products from the gut: What is important in human beings? Surgery 2002; 131: 241e4. 8 Cohen DB, Magnotti LJ, Lu Q, et al. Pancreatic duct ligation reduces lung injury following trauma and hemorrhagic shock. Ann Surg 2004; 240: 885e91. 9 Deitch EA. Role of the gut lymphatic system in multiple organ failure. Curr Opin Crit Care 2001; 7: 92e8. 10 Deitch EA, Xu D, Kaise VL. Role of the gut in the development of injury and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front Biosci 2006; 11: 520e8. 11 Gatt M. Gut failure: diagnosis and management (Doctoral Dissertation). Hull: University of Hull, 2008. 12 Gatt M, Reddy BS, Macfie J. Review article: bacterial translocation in the critically ill e evidence and methods of prevention. Aliment Pharmacol Ther 2007; 25: 741e57. 13 De Winter BY, De Man JG. Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility. World J Gastroenterol 2010; 16: 5523e35. 14 Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39: 165e228. 15 Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34: 17e60. 16 Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010; 36: 222e31.
Setting goals of care C Discuss goals of care and prognosis with patients and families. C Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. C Address goals of care as early as feasible, but no later than within 72 hours of ICU admission.
Box 3
thromboembolism as well as stress ulceration prophylaxis, amongst other therapies, needs to be given due consideration in the severely septic patient.
Conclusion The number of surgical patients developing sepsis due to disease or secondary to iatrogenic complications is significant. The resultant morbidity and mortality are immense, placing a huge burden on healthcare systems. There are many reasons for an inexorable rise in the prevalence of surgical sepsis and includes the increase in the size of the geriatric population, the epidemic of obesity and other chronic illnesses, the ever-increasing complexity of surgical procedures being performed as well as the emergence of antibiotic resistant pathogens, but to mention a few. The present understanding of the major causes of surgical sepsis is vast, albeit inadequate. The central role played by the gut is increasingly recognized, but poorly represented in the medical literature. Additionally, preventative strategies remain conspicuously ineffective. Severe sepsis, with its prohibitively high mortality rates, remains a major healthcare issue. Several complex immunopathological alterations to homeostasis are responsible for the associated morbidity and mortality figures. Although ongoing research has clarified some of the pathophysiological mechanisms involved, with the emergence of the central role of the gut
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situations, but none of the signs are specific enough to be pathognomonic on their own. A high degree of suspicion is required and the possibility of sepsis should be entertained when these signs are present.
Marcel Gatt
Abstract
Pathophysiology of sepsis
Sepsis is defined as the systemic inflammatory response syndrome (SIRS) associated with suspected or confirmed infection. As such, it is implicit that two components are necessary in the causation of surgical sepsis: a source of infection as well as a SIRS response by the patient. In recent years, the management of patients with sepsis has been aided by a much better understanding of the underlying pathophysiological processes which occur. In particular, we have a better perception of the complex interactions between the host and the invading organisms as well as a better appreciation of the cellular and extracellular pathways involved, including, but not confined to the complexly intertwined roles of the immunological system, the complement cascade and the coagulation pathway, as well as the role of the gut in driving this process. Given the plethora of homeostatic functions of the gastrointestinal tract, it is self evident, albeit somewhat poorly represented in the medical literature, that this organ plays a central role in the process. This article reviews the role played by the gut in the development of sepsis with a particular emphasis on the surgical patient. The passage of viable bacteria or its components across the gut barrier in a process known as bacterial translocation as well as other mechanisms are also discussed.
Homeostasis is maintained in vivo by a complex interplay of a number of mechanisms aimed at maintaining the status quo of the internal milieu. Such mechanisms include the immune system (with both its innate and adaptive components), as well as the complement and coagulation cascades. With respect to the immune system, a tightly maintained balance between opposing yet complimentary pro-inflammatory and anti-inflammatory mediators maintains health and homeostasis. Any upset in this tightly controlled balance may result in disease. The clinical manifestations of sepsis result from the complex interactions between the immune and other systems of the host and the infecting microorganisms. Cells of the host’s innate immune system recognize microorganisms and initiate responses to these microbes or their products. This response is mediated through a number of host cell surface receptors and proteins and a battery of microbe antigens. Host cell surface receptors include the so-called pattern recognition receptors (PRRs) and toll-like receptors (TLRs). These are expressed by cells of the innate immune system, which in turn employs a limited number of germline-encoded PRRs that recognize invariant pathogen-associated microbe antigens including small molecular motifs conserved within different classes of microbes known as pathogenassociated molecular patterns (PAMPs). Better known examples of PAMPs include lipopolysaccharides (LPS, endotoxins) expressed by virulent Gram-negative bacteria, peptidoglycan, lipopeptides, lipoteichoic acid (a component of gram-positive bacterial cell walls), flagellin and bacterial DNA. While it is beyond our scope to review the complexities of the immune system and other homeostatic pathways, it should suffice to say that activation of a variety of complex metabolic systems, including the immune and coagulation cascade pathways result from hosteantigen interaction, culminating in what is recognized as the septic response. With the involvement of such complex pathways and with the contribution of so many intermediate substances, one may be forgiven to think that the level of one or more of these intermediaries may be used to diagnose sepsis with some certainty or accurately monitor its progress. In the last few decades more than 170 biomarkers have been studied both as diagnostic markers as well as prognostic indicators for sepsis, but none of them have been found to have sufficient sensitivity or specificity on their own to be used routinely in clinical practice. CRP and procalcitonin (PCT) have been used most widely, but they both have their limitations when used to distinguish sepsis from other inflammatory conditions as well as when they are used as prognostic indices. In moderate to severe sepsis the inflammatory response causes an imbalance of procoagulants and anticoagulants, which culminates in disseminated intravascular coagulation (DIC). The formation of clots eventually cause thrombosis of small vessels and impaired tissue perfusion. The higher levels of cytokines and the secondary mediators in severe sepsis lead to hypotension due
Keywords Critically ill; gut failure; gut function; intestinal failure; mortality; multi-organ failure; multiple organ dysfunction syndrome; nutrition; sepsis; surgery; systemic inflammatory response syndrome
Introduction The word ‘sepsis’ is derived from Greek and means to decay or to make rotten. In modern practice, the phrase sepsis has come to represent a catch-all term referring to the changes observed when living organisms are subjected to an insult of an infectious nature. There have been many attempts to define sepsis more systematically1,2 and this has introduced a dizzying array of seemingly synonymous albeit novel and distinct concepts. Terms such as the systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) carry specific meanings and are often a source of confusion. For purposes of clarity, these and other relevant terms are summarized in Table 1. Despite numerous advances in clinical care, sepsis is widely recognized as a primary cause of morbidity and mortality in hospitalized patients. This is particularly true in the critically ill and the surgical patient. The diagnosis of infection and underlying sepsis in such patients can be complex, and the challenge is often intensified by multiple coexisting disease processes. The signs of sepsis suggested by the Sepsis Conference of 2001 and summarized in Table 2 are a useful guide to diagnosis in such
Marcel Gatt MD FRCS is a Consultant General and Colorectal Surgeon at the Combined Gastroenterology Research Unit, Scarborough General Hospital, York Teaching Hospitals NHS Foundation Trust, Scarborough, UK. Conflicts of interest: none declared.
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Definitions (adapted from3,4) Infection
Systemic inflammatory response syndrome (SIRS)
Sepsis Severe sepsis Septic shock
Multiple organ dysfunction syndrome (MODS)
A pathologic process caused by suspected or proven invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms or a clinical syndrome associated with a high probability of infection Presence of at least two or more of the following, one of which must be abnormal temperature or white blood cell (WBC) count in children: C Core temperature >38.3 C, >38.5 C in children, or <36 C C Heart rate >90 beats/minute or in children a mean heart rate >2 standard deviations (SD) above normal for age, or in children <1 year of age bradycardia defined as a mean heart rate <10th percentile for age C Respiratory rate >20 breaths/minute or PaCO2 <32 mmHg, or in children >2 SD above normal for age; or need for mechanical ventilation C WBC count >12,000/mm3 or <4000/mm3, or >10% immature (band) forms, or in children elevated or depressed level for age Systemic inflammatory response syndrome associated with suspected or confirmed infection, positive blood cultures are not necessary Sepsis complicated by cardiovascular organ dysfunction or acute respiratory distress syndrome or dysfunction of two or more other organs Cardiovascular collapse related to severe sepsis despite adequate fluid resuscitation characterized by hypotension defined as systolic blood pressure (SBP) <90 mmHg (in children a pressure <2 SD below normal for age), mean arterial pressure (MAP) <60 mmHg or a reduction of >40 mmHg on baseline SBP The presence of altered organ function in a patient who is acutely ill and homeostasis cannot be maintained without intervention. The criteria are: C Hypoxaemia (PaO2/FiO2 <300) C Acute oliguria (urine output <0.5 ml/kg/hour for 2 hours) or creatinine >2.0 mg/dl C Coagulopathy (platelet count <100,000, international normalized ratio >1.5 or partial thromboplastin time >60 seconds C Ileus C Plasma bilirubin >4 mg/dl
Table 1
to systemic vasodilation, diminished myocardial contractility, and systemic leucocyte adhesion due to widespread endothelial damage and activation as well as diffuse alveolar capillary damage in the lung. MODS ensues from these combined effects, most notably affecting the liver, kidneys and the central nervous system. In this situation, the patient can succumb rapidly unless the underlying infection (and the resulting LPS overload) is brought under control.2 It is increasingly recognized that the gut plays a pivotal role in both the initiation as well as the propagation of this septic response.
Typically, the numbers are lower in the stomach due to the hostile environment here. A low pH and slow transit promote the killing of ingested microbes. Ordinarily the proximal small bowel has fewer microbes than the distal small bowel and the number of microorganisms gets exponentially higher distal to the ileocaecal valve. The gut also serves as a barrier against luminal microbes and other antigens, essential in separating self from non-self; the so-called ‘intestinal barrier function’ of the gut. This barrier role of the gut is highly effective. The fact that luminal contents in the caecum have a bacterial concentration of the order of 1012 organisms/ml of faeces, whilst portal blood, mesenteric lymph nodes (MLN) and indeed tissues one cell deep to the intact intestinal mucosa are usually sterile, dramatically illustrates the efficacy of this barrier. Anaerobes are the predominant flora in the GI tract, outnumbering aerobes by approximately two orders of magnitude. The adherence of the resident gut microflora to endothelial cells, mucus and to each other creates a highly anaerobic environment which helps to prevent adherence, proliferation, overgrowth and invasion of pathogens. This phenomenon associated with the physical barrier is termed ‘colonization resistance’.5 The barrier role of the gut serves to manage luminal antigens, encouraging the symbiotic relationship between man and enteric bacteria without which humans could not survive, while ensuring that the internal milieu remains sterile. Breakdown or
Sepsis and the gut It is well established that the primary function of the gastrointestinal (GI) tract is that of nutrition, being involved in the digestion and absorption of nutrients, fluids and trace elements from the diet. The gut, however, is a highly complex organ and it satisfies a plethora of additional functions. Amongst other roles, it is also involved in the production of numerous hormones with both local and systemic effects, and participates in the excretion of waste by-products of metabolism. Its gut-associated lymphoid tissue (GALT) is the single largest immunological organ and cytokine producer in the body. The normal GI tract harbours large numbers of both aerobic and anaerobic bacteria which exist in symbiosis with man.
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The idea of bacterial translocation is not new. The notion that the alimentary tract, teeming with its own bacterial flora, could represent a source of sepsis under certain conditions has intrigued clinicians for many years. In 1891 and 1895, two separate investigators hypothesized that viable bacteria could pass through the intact gut wall in vivo. It was Berg and Garlington who in 1979 defined this phenomenon as ‘bacterial translocation’. Nowadays, bacterial translocation is used to describe the passage of viable resident bacteria from the gastrointestinal tract, across the gut mucosa, to normally sterile tissues such as the MLN and other internal organs. The term also applies to the passage of inert particles and other antigenic macromolecules, such as lipopolysaccharides (LPS), endotoxins and peptidoglycans, across the intestinal mucosal barrier.6 In this respect, the gut can be considered both as a target organ for pathogens as well as a source of pathogenic organisms. This role of the gut as the so called ‘undrained abscess’ or ‘motor’ of multiple organ failure has been used to explain the absence of a discreet focus of infection in most patients with delayed SIRS and MODS, particularly prevalent in those with prolonged critical illness. Numerous modifications to the ‘gut origin of sepsis hypothesis’ have been put forward to attempt to define this process of gut-derived sepsis. Deitch proposed the ‘multi-hit model’7,8 wherein an initial insult results in splanchnic hypoperfusion (first hit) with the gut becoming a major site of pro-inflammatory factor production. Resuscitation results in reperfusion which leads to an ischaemia-reperfusion injury to the intestine (second hit) with a resultant loss of gut barrier function and an ensuing enhanced gut inflammatory response, without the need for translocation of microbes as far as the MLN or beyond. Once bacteria or endotoxin cross the mucosal barrier, they can trigger an augmented immune response such that the gut becomes a pro-inflammatory organ, releasing chemokines, cytokines and other pro-inflammatory intermediates which affect both the local as well as the systemic immune systems (third hit), finally resulting in SIRS and MODS. Another modification of the ‘gut origin of sepsis hypothesis’ is known as the ‘gut-lymph theory’9,10 which proposes that macrophages and other immune cells in the submucosal lymphatics of the gut wall or the MLN trap the majority of translocating bacteria. However, those that survive, or the cell wall and protein components of the dead bacteria (including lipopolysaccharides and peptidoglycans) along with the cytokines and chemokines generated in the gut, travel via the mesenteric lymphatics to the cysterna chyli, and via the thoracic duct empty into the left subclavian vein to reach the right side of the heart. These inflammatory products then enter the pulmonary circulation and activate the alveolar macrophages. In so doing, they contribute to acute lung injury and the progression to acute respiratory distress syndrome (ARDS) and MODS. If nothing else, the number of existing theories is testament to the fact that the underlying mechanisms involved are poorly understood. Indeed, whist it is tempting to think that any bacteria or endotoxin passing through the intestinal barrier might cause septic complications in the host, there is growing evidence to the contrary and that translocation may in fact be a normal ubiquitous phenomenon. It is possible that translocation occurs to allow the alimentary tract to be exposed to and sample antigens within the lumen such that the gut can mount a controlled local
Signs of sepsis (adapted from3) General signs and symptoms
C C C C C
Generalized haematological/inflammatory reaction
C
Haemodynamic alterations
C
C
C C
C C C
Signs of organ dysfunction
C C C
C C C
C
Rigours Fever or hypothermia Tachypnoea/respiratory alkalosis Positive fluid balance Oedema Increased or decreased WBC count Increased inflammatory markers (CRP, PCT, IL-6) Arterial hypotension, Unexplained tachycardia Increased cardiac output/low systemic vascular resistance/high SvO2 Altered skin perfusion Decreased urine output Unexplained hyperlactaemia/increased base deficit Hypoxaemia (acute lung injury) Altered mental status Unexplained alteration in renal function Hyperglycaemia Thrombocytopenia/DIC Unexplained alteration in liver function tests Intolerance to feeding
CRP, C-reactive protein; DIC, disseminated intravascular coagulation; IL-6, interleukin-6; PCT, procalcitonin; SvO2, mixed venous oxygen saturation; WBC, white blood cell.
Table 2
overwhelming of this barrier may result in the ingress of viable bacteria and their antigens with the development of sepsis, initiation of a cytokine-mediated SIRS, MODS, and death. In summary, the gut has many functions that are essential to maintaining homeostasis, without which survival would be, at best, difficult, if not impossible. Because of these numerous homeostatic functions, it is increasingly recognized that the gut plays a pivotal role in the development and propagation of sepsis. In particular, breakdown or overwhelming of gut barrier function may result in the ingress of viable bacteria and their antigens with the development of sepsis, initiation of a cytokinemediated SIRS, MODS, and eventually death. This process whereby bacteria or their products breach the gut barrier is known as ‘bacterial translocation’ and describes the so called ‘gut origin of sepsis hypothesis’.
The gut barrier, bacterial translocation, oral tolerance and gut dysfunction Theories relating to the initiation and propagation of sepsis by the gut abound. The most widely accepted mechanism centres around the translocation of bacteria and/or their products from the lumen of the gut into the internal milieu.
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do not induce bacterial translocation. Alterations in mucosal architecture or intestinal permeability may indicate certain changes in intestinal barrier function but do not necessarily equate with alterations in the prevalence of bacterial translocation or sepsis. As such, the nature of the nutritional support that should be provided to patients should be determined by their tolerance to EN and not by unfounded fears regarding TPN or unjustified assumptions concerning the role of gut barrier function.12 In this respect, if TPN is necessary it should not be withheld on the wrong assumption that it will promote bacterial translocation. It is self evident, however, that maintaining patients on EN requires a functioning gut. As such, one true advantage of EN over TPN, other than cost, lies in the fact that tolerance to EN can be used to assess underlying gut function. There is also some evidence that EN may decrease the prevalence of stress ulceration, but clearly whether this is a direct result of EN administration, or simply because EN is only possible in a wellfunctioning gut (whose repair and barrier mechanisms are intact), remains somewhat controversial. As a functioning gastrointestinal tract remains an essential prerequisite for maintaining the integrity of the immune system and gut barrier function, and this has a direct effect on sepsis, it remains logical to institute EN whenever possible, but without withholding TPN when this becomes necessary. Gut hypoperfusion and subsequent reperfusion injury are thought to represent important early sources of pro-inflammatory mediators. Both events trigger activation of stress sensitive protein kinases that converge on transcription factors, which regulate the expression of pro-inflammatory genes. Pro-inflammatory mediators and cytokines generated in the gut reach the circulation via intestinal lymphatics. Even when the bacteria or bacterial products are trapped in the gastrointestinal wall or intestinal lymph nodes not reaching the systemic circulation, they increase the inflammatory response of the gut. Studies in animal models have shown a complex interplay within the gastrointestinal wall between mast cells, macrophages and glial cells on one hand, and neurons and smooth muscle cells on the other, involving intracellular signalling pathways, cytokines, mediators in afferent neuronal signalling and anti-inflammatory vagal pathway. As these mechanisms are being elucidated further, they have also led to increased interests in research on antiinflammatory and prokinetic drugs in preventative strategy against multi-organ failure.13 In view of the methodological problems in confirming bacterial translocation as a measure of gut barrier function, in vivo investigations in humans have had to be restricted to patients undergoing laparotomy during which MLN can be sampled. As such there is only limited data available relating to specific interventions which might preserve intestinal barrier function or limit bacterial translocation. Based on the best currently available knowledge, glutamine supplementation, aggressive and targeted nutritional intervention, maintaining good splanchnic flow whilst limiting other inotropic support, the judicious use of antibiotics and directed selective gut decontamination regimes, amongst other interventions hold some promise of attenuating gut failure or enhancing the return of gut function.12 In so doing, they may limit bacterial translocation, as an epiphenomenon associated with gut barrier dysfunction. Whether these and other
immune response helping to keep these antigens away from the internal milieu, a process known as ‘oral tolerance’. It is then only when the host’s immune defences are overwhelmed, attenuated or otherwise defective that septic complications arise. This failure of the gut barrier is one of the manifestations of gut dysfunction, and in this setting bacterial translocation represents little more than an epiphenomenon of gut barrier dysfunction. In humans, the most reliable method of assessing bacterial translocation is by culture of MLN. This involves the limited sampling of MLNs at the time of laparotomy using aseptic techniques, and their subsequent culture. A positive culture is considered to indicate bacterial translocation. It is important to emphasize that, given the obvious limitations pertaining to MLN harvest and subsequent culture, the literature is full of studies using surrogate measures of intestinal barrier function. These include blood cultures with concomitant faecal cultures, intestinal immune markers, bowel scrapings, intestinal permeability measurements, the culture of nasogastric aspirates, assessment of villous height and many others. It is felt that these do not represent good surrogates of bacterial translocation nor of intestinal barrier function, and as such the findings of such studies should be interpreted with great caution. Implicit to the many homeostatic roles of the gastrointestinal tract is the recognition that gut dysfunction (such as occurs in the setting of ileus for example) or gut failure will result in poorer patient outcomes.11 As gut dysfunction and failure is closely linked with the need for total parenteral nutrition (TPN), many have made the error of associating poorer outcomes (especially septic complications) which are sometimes recorded in patients receiving TPN with the administration of TPN itself. This has resulted in misconstrued avoidance of TPN especially in critically ill patients most at risk of both malnutrition and net nitrogen loss, hence arguably those patients which need adjuvant nutritional support the most. Fortunately, this misplaced concern that TPN may increase sepsis is recognized and is being readdressed. Today there is increased recognition that higher levels of sepsis previously noted in patients receiving TPN related to other factors. These included hyperglycaemia from erroneous overfeeding and also the recognition that gut failure (and subsequently failure of gut barrier function) itself predisposed to both the higher levels of sepsis as well as the subsequent need for TPN. In this respect, TPN is an innocent confounding factor of sepsis.12 It is widely recognized that early institution of nutritional support is of benefit, particularly in patients with severe infirmity. Not surprisingly, most reviewers of nutritional support therapy urge the use of enteral nutrition (EN) as opposed to TPN given the aforementioned (and other) falsely held concerns about TPN. It is often believed that TPN results in mucosal atrophy, increased intestinal permeability, and other deleterious effects on the gut and reflect damage to the intestinal barrier. Similarly, it is often reported that luminal nutrients during EN have the opposite effect. There is no evidence to suggest that in humans bacterial translocation is reduced by the use of EN, that short-term (21 days) TPN is associated with villus atrophy or significant changes in intestinal permeability or indeed that alterations in intestinal permeability will, in turn, predispose to an increased prevalence of bacterial translocation or sepsis.12 Starvation, malnutrition, or the absence of luminal nutrients by themselves
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gut-directed interventions will decrease sepsis or attenuate the SIRS response remains to be seen. Future potential in preserving intestinal barrier function may lie in targeted immunomodulation of the gut-associated lymphoid tissue as well as other gutdirected therapies aimed at attenuating gut failure. The fact remains that the gut is increasingly recognized as having a pivotal role in the onset and propagation of sepsis, albeit underrepresented in published medical literature. Testament to this underrepresentation is the absence of gut-related parameters from most, if not all, clinical outcome scoring systems (e.g. APACHE, POSSUM, SOFA), with barely a mention in the most recent issue of the ’surviving sepsis campaign’ (SCC).14 Many of the mechanisms involved remain poorly appreciated, and a better understanding in this respect may help delay or prevent the onset of SIRS and MODS, ultimately improving outcomes especially in critically ill and surgical patients.
Initial resuscitation and infection issues (adapted from14) Initial resuscitation C Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion. C Goals during the first 6 hours of resuscitation: central venous pressure 8e12 mm Hg mean arterial pressure (MAP) 65 mm Hg urine output 0.5 mL/kg/hour central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively. C
Screening for sepsis and performance improvement C Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy. C Hospitalebased performance improvement efforts in severe sepsis.
The ‘surviving sepsis campaign’ (SSC) and the management of sepsis The SSC is an international effort by a group of experts in the field aimed at increasing awareness of and improving outcomes in severe sepsis. In 2004 the group published the first internationally accepted guidelines that clinician could use by the bedside to improve outcomes in patients with severe sepsis and septic shock. In 2008 an updated guideline was published using a new evidence based methodology for assessing the quality of evidence and the strength of recommendations based on this evidence.15 The latest version of these guidelines has only recently been published in 2013 following a consensus conference in 2012.14 In essence, the SCC recommends the use of a number of ‘care bundles’ intended on improving outcomes in septic patients. It must be emphasized that the recommendations from these guidelines cannot replace the decision-making ability of the clinicians when faced with an individual patient’s unique set of clinical variables both on the intensive care unit (ICU) and nonICU settings.15 There are many critics of the SSC recommendations who find the grouped therapies or ‘care bundles’ for particular subset of patients to be somewhat didactic and often lacking in evidence. Nonetheless, there is some evidence that the process of care and outcomes have improved after educational programmes were instituted based on the various incarnations of the SSC and its care bundles.16 However, the persistent lack of emphasis on the pivotal role played by the gut, and tailored therapies to target gut dysfunction remains a concern. The clinical recommendations in order to achieve a significant (estimated at approximately 25%) reduction in mortality from severe sepsis are summarized in Boxes 1 to 3 and are adapted directly from the SCC.14 These include care bundles aimed at the initial resuscitation phase, which should also include source control of infection, and administration of antibiotics. The recognition that haemodynamic support to include the appropriate use of directed fluid therapy, vasopressor and inotropic agents, as well as steroids is similarly essential. Finally, other supportive therapies such as the targeted use of blood and blood products, specific mechanical ventilation in sepsis, the use of analgesics and sedation, glycaemic control, renal replacement therapy, nutritional support and the use of deep venous
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In patients with elevated lactate levels, target resuscitation to normalize lactate.
Diagnosis C Cultures as clinically appropriate before antimicrobial therapy if no significant delay (>45 minutes) in the start of antimicrobial(s). C At least two sets of blood cultures (both aerobic and anaerobic bottles) to be obtained before antimicrobial therapy. C Ensure invasive candidiasis is included in the differential diagnosis of cause of infection. C Imaging studies performed promptly to confirm a potential source of infection. Antimicrobial therapy C Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis. C Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis. C Antimicrobial regimen should be reassessed daily for potential de-escalation. C Discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection. C Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multi drug resistant bacterial pathogens. C Empiric combination therapy should not be administered for more than 3e5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. C Duration of therapy typically 7e10 days; longer courses may be appropriate in some patients. C Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin.
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C
Vasopressors C Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg. C Norepinephrine as the first choice vasopressor. C Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. C Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage. C Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03e0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents). C Dopamine as an alternative vasopressor agent to norepinephrine to be used only in highly selected patients (e.g. patients with low risk of tachyarrhythmias and absolute or relative bradycardia). C Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. C Low-dose dopamine should not be used for renal protection. C All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.
Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause.
Source control C A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hours after the diagnosis is made, if feasible. C When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (e.g. percutaneous rather than surgical drainage of an abscess). C If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established. Infection prevention C Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia. C Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilatorassociated pneumonia in ICU patients with severe sepsis.
Box 1
Inotropic therapy C A trial of dobutamine infusion up to 20 micrograms/kg/min should be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. C Do not use a strategy to increase cardiac index to predetermined supranormal levels.
Haemodynamic support and Adjunctive Therapy recommendations (adapted from14) Fluid therapy of severe sepsis C Use crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. C Do not use hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. C Use albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. C Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolaemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. C A fluid challenge technique should be applied wherein fluid administration is continued as long as there is haemodynamic improvement either based on dynamic (e.g. change in pulse pressure, stroke volume variation) or static (e.g. arterial pressure, heart rate) variables.
Corticosteroids C Do not use intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore haemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, suggest intravenous hydrocortisone alone at a dose of 200 mg per day. C Do not use the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. C Taper hydrocortisone in treated patients when vasopressors are no longer required. C Do not administer corticosteroids for the treatment of sepsis in the absence of shock. C When hydrocortisone is given, use continuous flow.
Box 2
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Other Supportive Therapy of Severe Sepsis recommendations (adapted from14) C
Blood product administration C Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, (such as myocardial ischaemia), red blood cell transfusion should occur only when haemoglobin concentration decreases to <7.0 g/dL to target a haemoglobin concentration of 7.0e9.0 g/dL in adults. C Do not use erythropoietin as a specific treatment of anaemia associated with severe sepsis. C Fresh frozen plasma should not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. C In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 109/L) in the absence of apparent bleeding.
Glucose control C Employ a protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose 180 mg/dL rather than an upper target blood glucose 110 mg/dL. C Monitor blood glucose values every 1e2 hours until glucose values and insulin infusion rates are stable and then every 4 hours thereafter. C Interpreted glucose levels obtained with point-of-care testing of capillary blood with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values.
Immunoglobulins C Do not routinely use intravenous immunoglobulins in adult patients with severe sepsis or septic shock.
Renal replacement therapy C Continuous renal replacement therapies and intermittent haemodialysis are equivalent in patients with severe sepsis and acute renal failure. C Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients.
Selenium C Do not use intravenous selenium for the treatment of severe sepsis. Mechanical ventilation of sepsis-Induced acute respiratory distress syndrome (ARDS) C Target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS. C Plateau pressures should be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung should be 30 cm H2O. C Positive end-expiratory pressure (PEEP) should be applied to avoid alveolar collapse at end expiration. C Prone positioning should be used in sepsis-induced ARDS patients with a PaO2/FiO2 ratio 100 mm Hg in facilities that have experience with such practices. C Mechanically ventilated sepsis patients should be maintained with the head of the bed elevated to 30e45 degrees to limit aspiration risk. C A weaning protocol should be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy set criteria. C Avoid the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS. C Employ a conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion.
Bicarbonate therapy C Do not use sodium bicarbonate therapy for the purpose of improving haemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidaemia with pH 7.15. Deep vein thrombosis prophylaxis C Prescribe patients with severe sepsis daily pharmacoprophylaxis against venous thromboembolism (VTE). This should be accomplished with daily subcutaneous lowmolecular weight heparin (LMWH). If creatinine clearance is <30 mL/minute, use dalteparin or another form of LMWH that has a low degree of renal metabolism or UFH. C Treated patients with severe sepsis with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible. C Septic patients who have a contraindication for heparin use (e.g. thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral haemorrhage) should not receive pharmacoprophylaxis, but receive mechanical prophylactic treatment, such as graduated compression stockings or intermittent compression devices, unless contraindicated. When the risk decreases start pharmacoprophylaxis. Stress ulcer prophylaxis C Prescribe stress ulcer prophylaxis using H2 blocker or proton pump inhibitor to patients with severe sepsis/septic shock who have bleeding risk factors. C When stress ulcer prophylaxis is used, use proton pump inhibitors rather than H2RA. C Patients without risk factors do not require prophylaxis.
Sedation, analgesia, and neuromuscular blockade in sepsis C Minimize the use of continuous or intermittent sedation in mechanically ventilated sepsis patients, targeting specific titration endpoints. C Avoid neuromuscular blocking agents (NMBAs) if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs
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must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used. Employ a short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a PaO2/FiO2 <150 mm Hg.
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in the initiation and propagation of some episodes of sepsis, much still remains to be understood in the expectation that effective therapies can be developed to improve the survival from sepsis. There remains much scope for research in this field aimed primarily at a better understanding of the mechanisms involved in causing surgical sepsis, and developing ways to prevent it. A
Nutrition C Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock. C Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (e.g. up to 500 calories per day), advancing only as tolerated. C Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock. C Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis.
REFERENCES 1 Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Med 2002; 28: 824e33. 2 Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765e77. 3 Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 2003; 29: 530e8. 4 Goldstein B, Giroir B, Randolph A. International paediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in paediatrics. Pediatr Crit Care Med 2005; 6. 5 Dunn DL. Autochthonous microflora of the gastrointestinal tract. Perspect Colon Rectal Surg 1990; 2: 105e19. 6 Gatt M, Macfie J. Bacterial translocation in surgical patients. In: . Recent advances in surgery, vol. 28. London: The Royal Society of Medicine Press Limited, 2005; 23e32. 7 Deitch EA. Bacterial translocation or lymphatic drainage of toxic products from the gut: What is important in human beings? Surgery 2002; 131: 241e4. 8 Cohen DB, Magnotti LJ, Lu Q, et al. Pancreatic duct ligation reduces lung injury following trauma and hemorrhagic shock. Ann Surg 2004; 240: 885e91. 9 Deitch EA. Role of the gut lymphatic system in multiple organ failure. Curr Opin Crit Care 2001; 7: 92e8. 10 Deitch EA, Xu D, Kaise VL. Role of the gut in the development of injury and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front Biosci 2006; 11: 520e8. 11 Gatt M. Gut failure: diagnosis and management (Doctoral Dissertation). Hull: University of Hull, 2008. 12 Gatt M, Reddy BS, Macfie J. Review article: bacterial translocation in the critically ill e evidence and methods of prevention. Aliment Pharmacol Ther 2007; 25: 741e57. 13 De Winter BY, De Man JG. Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility. World J Gastroenterol 2010; 16: 5523e35. 14 Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39: 165e228. 15 Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34: 17e60. 16 Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010; 36: 222e31.
Setting goals of care C Discuss goals of care and prognosis with patients and families. C Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. C Address goals of care as early as feasible, but no later than within 72 hours of ICU admission.
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thromboembolism as well as stress ulceration prophylaxis, amongst other therapies, needs to be given due consideration in the severely septic patient.
Conclusion The number of surgical patients developing sepsis due to disease or secondary to iatrogenic complications is significant. The resultant morbidity and mortality are immense, placing a huge burden on healthcare systems. There are many reasons for an inexorable rise in the prevalence of surgical sepsis and includes the increase in the size of the geriatric population, the epidemic of obesity and other chronic illnesses, the ever-increasing complexity of surgical procedures being performed as well as the emergence of antibiotic resistant pathogens, but to mention a few. The present understanding of the major causes of surgical sepsis is vast, albeit inadequate. The central role played by the gut is increasingly recognized, but poorly represented in the medical literature. Additionally, preventative strategies remain conspicuously ineffective. Severe sepsis, with its prohibitively high mortality rates, remains a major healthcare issue. Several complex immunopathological alterations to homeostasis are responsible for the associated morbidity and mortality figures. Although ongoing research has clarified some of the pathophysiological mechanisms involved, with the emergence of the central role of the gut
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