GM Clarke Sepsis has traditionally implied infection accomp anied by systemic inflammatory manifestations.

However, the systemic changes are indistinguishable from those of noninfective inflammatory conditions (e.g. pancreatitis, acute hepatic failure, immunol ogical reactions and gross trauma including bums). Consequently, much confusion arose when terms such as sepsis and septic syndrome were applied to these conditions.1 This led to a consensus conference of the American College of Chest Physicians and Society of Critical Care Medicine to define terms related to infection and the systemic response (Table 61.1; Fig. 61.l).2 Thus, sepsis is the systemic inflammatory respanse to infection. It is the comm onest contributor to death in the ICU.3 Aetiology and epidemiology Sepsis may be caused by Gram-negative and Gram- positive bacteria, fungi, Rickettsia, viruses and spiro chaetes. In the ICU, common infective Gram- negative organisms include Escherichia coli, Pseudomonas, Kiebsiella, Proteus, Enterobacter and Bacteroides; Grampositive organisms include stap hylococci, streptococci and Clostridium. Systemic infection with fungi, especially Candida, is a risk in immunodeficient patients receiving broadspectrum antibiotics. The EPIC study reported that 17% of ICU patients had fungal and/or protozoal infection.4 Nosocomial infection rates in ICU patients are 510 times higher than among general ward patients. Organisms posing serious resistance problems in the rcu setting include methicillinresistant staphyloc occi, enterococci, certain Enterobacteriaceae, Pseud omonas aeruginosa, P cepacia, Xanthomonas malt ophilia, Acinetobacter and Candida species.5 danv infcction acquircd in hc IC .irc iidogen ous and follow colonization of the alimentary tract by organisms usually insignificant in healthy individu als (e.g. E. coli, Kiebsiella, Proteus and Pseudomon as).6 Sepsis related to intravascular catheters is commonly due to Staphylococcus epidermidjs, a normal skin commensal. Pathogenesis The host response, rather than the infecting organism, predominantly determines the severity of an infect ion.7 Pathogenesis of the extremely complex syst emic inflammatory response involves host defence mechanisms, products of infecting organisms (e.g. exotoxins and endotoxins) and a multitude of mediat ors (Fig. 61.2). Host defence mechanisms

Local organ defences These may be impaired by critical illness or therap eutic interventions. Respiratory system Coughing may be impaired by pain, illness or drugs. The mucociliary escalator system may be depressed by opioids, aspirin, inspired oxygen, inadequate humidification or endotracheal suctioning. Laryngeal dysfunction, from neurological dysfunction, drugs or nasogastric or endotracheal tubes, can lead to aspiration. Alimentary tract Gastrointestinal tract (GIT) mucosa and motility, secretion of mucus and immunoglobulin A, and indigenous anaerobes resist gut colonization by aerobic bactena.6 GIT flora may rapidly alter in the ICU patient. Following hospitalization, mouth flora changes from predominantly anaerobic to Gramn egatis C organisms such ON E. to/i. Kiebsiella and Pseudomonas. Staphylococcus aureus and Candida albicans may become part of the flora. The stomach, which is normally sterile, becomes colonized with similar organisms if the gastric p1-I is above 4.0 Table 61.1 Definitions of sepsis2 Infection Microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those olganisms Bacteraem,a The presence of viable bacteria in the blood Systemic inflamniarory response syndrome The systemic inflammatory response to a vanety of severe clinical insults. The response is manifested by two or more of the following conditions: Temperature >38C or <36C Heart rate >90 beats/mm Respiratory rate >20 breaths/rain or Paco2 <4.3 kPa (<32 Torr) White blood cell count >12000 cells/mm3, or> 10% immature (band) forms Sepsis The systemic response to infection. This systemic response is manifested by two or more of the following conditions as a result of infection: Temperature >38C or <36C

Heart rate >90 beats/mm Respiratory rate >20 breaths/mm or Paco2 <4.3 kPa (<32 Torr) White blood cell count >12 000 cells/mm3, or> 10% immature (band) forms Severe sepsis Sepsis associated with organ dysfunction, hypoperfusjon or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria or an acute alteration in mental status Septic shock Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited 10, lactic acidosis, oliguria or an acute alteration in menta] status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time when perfusion abnormalities are measured Hypotension A systolic blood pressure of <90 mnilig or a reduction of>40 mmFlg from baseline in the absence of other causes for hypotension Multiple organ dysfunction syndrome Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. Fig. 61.1 Interrelationship of systemic inflammatory response syndrome (SIRS), sepsis and infection. From American College of Chest Physicians/Society of Critical Care Medicine,2 with permission. 526 61 Severe sepsis Insult I macrophage/monocyte activation I Interleu kin-i

TN F Others + Systemic inflammatory response (if very severe) Tissue damage Altered haemodynamics Altered cellular metabolism NO1SVR Impaired oxygen extraction I Multiple organ dysfunction syndrome Fig. 61.2 Simplified scheme of events from insult to systemic inflammatory respons{ to multiple organ dysfunction syndrome. TNF = Tumour necrosis factor; NO = nitric oxide; SVR = systemic vascular resistance. likely if antacids or H2-blockers are prescribed. Antibiotics rapidly alter normal gut flora. Overgrowth of Candida is common; overgrowth with Clostridium d/ficile in the large bowel, though uncommon, may cause pseudomembranous colitis due to its toxins. Eyes Impaired blinking results in drying of cornea and conjunctiva. Loss of the irrigating and antibacterial properties of tears predisposes to infection. Genitourinary tract The uredwal catheter is a common route of urinary tract infection, especially by perineal faecal bacteria. Skin This may be breached by invasive catheters, all of which increase the risk of infection from skin organisms. General body defence mechanisms

Defects in immune competence are frequently seen in the critically ill (see Chapters 59 and 90). Some defects are set out below, but considerable overlap and interaction occur. Reticuloendothelial system Reticuloendothelial blockade results in defective phagocytic activity. This is partly related to ]owered opsonh aLtivit3 i.e. promotion ol phagocytosis is decreased). Sepsis itself can result in consumption of opsonic proteins, termed consumptive opsoninopathy. Apart from diminished phagocytic activity, defects in polymorph chemotaxis and intracellular killing may be present. Cell-mediated immunity Anergy (failure of delayed hypersensitivity), possibly reflecting defective T-helper cell function, has proven to be a marker for altered host resistance, sepsis and mortality in surgical patients.8 Age, cancer, sepsis, major trauma, malnutrition and increased T-supp ressor cell activity have been implicated.8 The presence of a T-cell suppressive factor (possibly a peptide) has been demonstrated in sera of trauma and cancer patients.9 Steroids, immunosuppressive agents, halothane and antibiotics (e.g. tetracycline, chioramphenicol and clindamycin) may Impair ccll ular immunity. Protein-calorie malnutrition may be associated with anergy, diminished complement leve ls and impaired immunoglobulin synthesis.1 Infections by well-encapsulated bacteria (e.g. stap hylococci and streptococci) are generally handled by humoral defence mechanisms. Cell-mediated immun ity is important in infections by poorly encapsulated Gram-negative organisms, such as Pseudomontis and intestinal anaerobes common causes of severe sepsis in the critically ill. Humoral immunity Defects in humoral immunity are seen in posts plenectomy patients) Immunoglobulin (especially immunoglobulin M; 1gM) and complement defic iencies and diminished properdin activity have been reported in these patients. The latter alternative complement pathway factor is important, as pneumoc occi are more efficiently opsonized via the altern ative pathway in the immunedeficient host. The asplenic patient is thus predisposed to overwhelming bacterial sepsis, with pneumococci, Neisseria mening itidis, E. coli, Haemophilus influenzae and Staphyloc occus aureus having been reported. The risk of splenectomy-associated sepsis is considerably higher in trauma than in Hodgkins disease, idiopathic thrombocytopenia and acquired haemolytic anaemic. Exotoxins Exotoxins are products of microorganisms harmful to the host, usually being high-molecular-

weight, heat- labile and antigenic proteins. (The toxins of Staphyloc occus are poorly antigenic; fungal toxins are nona ntigenic of low molecular weight.2) Some bacteria produce only one significant toxin to cause disease (e.g. tetanus, diphtheria, cholera and botulism). Other bacteria may produce an array of toxins, the significance and action of many being ill understood (e.g. Staphylococcus, Streptococcus and Clostridiun perfringen.r). A group may harm the host throiith thc actions of both cxoloxins and cttdotoxins (e.g. Pseudomonas). Endotoxin Endotoxin is part of the outer membrane of Gram- negative bacteria. Whereas exotoxins are heat-labile proteins, endotoxin is a lipopolysaccharide (LPS) and is much more heat-stable. LPS is known to consist I a lipid moiety (lipid A) which is responsible for most, if not all of the biological activity of bacterial endotoxin; 2 a core polysaccharide; 3 oligosaccharide side chains which confer 0-antig en specificity to the molecule and differ widely from strain to strain. However, core polysaccharidelipid A complexes of most Gram-negative bacteria are very similar in structure. Reasons given for implicating LPS in the pathophysiology of Gramnegative sepsis include the following: 1 Endotoxins on the surface of circulating bacteria are in a position to activate biological mediators of shock, even if endotoxin is below detectable levels. 2 Clinical features of Gram-negative bacteraemia are identical to the effects of endotoxin administered Iv. 3 Antibiotics cannot reverse, and may possibly even aggravate, these features when bacteria are killed. Mediators4 There are over 100 known mediators which may be involved in the systemic inflammatory response. Known important ones are listed in Table 61.2. Some cytokines exist in both circulatory and cell-associated forms (e.g. interleukin- 1 (IL- 1), tumour necrosis factor (TNF)). Actions and interactions are complex, with some mediators inducing the release of

others. A variety of feedback systems moderate the whole response. Primary mediators such as TNF can induce toxic responses by activating neutrophils and the coagulation system, and endothelial cells to produce nitric oi4e(NO; see below). Natural inhibitors also exist, e.g. Ciesterase inhibitors, soluble TNF recept ors and IL-i receptor antagonists (IL-Ira). IL-lO is a potent macrophage-deactivating factor inhibiting the production of TNF and interferon--y (IFN-y). IL-4, being a primary B-cell stimulant, reduces IL-I and TNF production, and is thus anti-inflammatory. Table 61.2 Important mediators in severe sepsis Cytokines (e.g. tumour necrosis factor. interleukins. intcrfernComplement system Contact system and extrinsic pathways of coagulation Fibrinolytic system Cells such as mononuclears. macrophages, microphages (predominantly neutrophils), endothelial cells and platelets Prostaglandin Leukotrienes Platelet-activating factor Oxygen free radicals Proteases Nitric oxide Cardiovascular pathophysiology The systemic response of sepsis has significant cardiovascular effects which reflect some of the pathogenetic mechanisms. Systemic vascular resistance Severe sepsis is commonly associated with a decreased systemic vascular resistance index (SVRI), which results in hypotension despite- a normal or increased cardiac index (G1).5 This is now believed to be due principally to NO production in endothelial and vascular smooth muscle cells, via NO synthase, an enzyme that can be induced by endotoxin and certain cytokines (e.g. IFN-y, TNF and some interl eukins).6 Other mediators implicated include histam ine, 3-endorphins, decreased C3 complement, C3 proactivator and decreased prekallikrein.7 Most non- survivors of severe sepsis show persistent vasodilatat ion with refractory hypotension.

Venous capacitance Increased venous capacitance, due to decreased venous tone (probably due to increased NO product ion), results in relative hypovolaemia. Pulmonary vascular resistance (PVR) PVR may be normal initially, but frequently rises at a later stage of sepsis.8 The mechanisms of increased PVR are ill understood; PVR may still be increased in the absence of hypoxaemia or acidosis. Postulated causative factors include microthrombi, vasoactive amine, endotoxin, angiotensin, platelet-activating 528 factor (PAF), thromboxane A2 and endothelin- I. Increased PVR has been associated with increased mortality. 8 Capillary permeability Capillary permeability of both systemic and pulmon ary capillary beds may increase rapidly so that fluid is lost from the circulation. Clearance of radioi odinated serum albumin has been shown to increase from a normal of 510%/h to 2035%/h in severe sepsis. 9 Myocardial function Myocardial dysfunction is common with severe sepsis and is usually associated with high mortality. Radionuclide scans showed that survivors had an initially depressed biventricular ejection fraction with biventricular dilatation.2 These changes returned towards normal over 710 days with recovery. Non- survivors had minimally increased biventricular eject ion fraction and ventricular size, without significant change over time, and most died of refractory hypotension. Why functionally worse patients parad oxically survived is not clear; ventricular dilatation may be a beneficial compensatory mechanism to improve stroke voume. Possible causes of myocardial dysfunction include a myocardial depressant factor (MDF) and diminv 02 ished coronary blood flow.7 The latter is not supported by coronary sinus catheter studies reporti ng normal mvocardial blood flow and increased niyocardial Ia.aatc uptake. Systemic acidosis and hypoxaemia will have added delterious effects on myocardial function. Some mediators (e.g. fNF and PAF) directly or indirectly depress the myocardiuni. TNF and IL-i inhibit myocardial respones to f3-adrenergic stimulation.14 In vitro studies have also implicated NO.23

Global oxygen transport and consumption In severe sepsis, and especially in septic shock, there are major disturbances in oxygen transport and consumption. Correction of hypovolaemi usdally results in a hyperdynamic circulation high CL and low SVRI. Oxygen consumption (Vo2) is frequently normal or decreased relative to metabolic demands.2 None the less, the presence of hyperlactic acidaemie suggests inadequate oxygen delivery (Do2) and utilization in some regional vascular beds.2526 Decreased oxygen extraction (i.e. increased mixed venous oxygen saturation with decreased arteriov enous oxygen difference) is a common finding. This may result from peripheral arteriovenous shunts (due to maldistribution of blood flow secondary to impaired vasoregulation and interstitial oedema), and cellular metabolic defects limiting the cells ability to utilize oxygen. Acutely Ill Patients ? CoMfinued Supely . Dependency SUPI* Independent Supptj Dependent DO2 Nomial Subjects Fig. 61.3 Relationship of oxygen consumption (Vo2) to oxygen delivery (Do2). injections ana immune aisoruers The concept of pathological supply dependency of oxygen uptake (reflected by Vo2) on oxygen delivery has been proposed in sepsis (Fig. 61.3)2728 Vo2 is dependent on Do,. denoting inadequate oxygen upp1y to tissue. Thus, the implication is to use high (supranormal) Do2 and haemodynamic values as therapeutic targets (see below). However, this supply dependency concept has not been demonstrated in more recent studies (see below and Chapter 22). Also, should oxygen demand vary (as it does in a febrile, septic, restless patient) then oxygen supply is expected to co-vary, i.e. Do2 would follow or be dependent

uon Vo2 (as in exercise), and not the other way around. Regional perfusion and oxygen consumption Regional changes in oxygen transport in septic shock cannot be predicted from whole-body changes. Splanchnic blood flow, oxygen extraction and Vo2 can increase during the acute phase of septic shock, despite reduced whole-body oxygen extraction.3 This marked splanchnic hyperrnetabolism may cont ribute to a regional mismatch between oxygen demand and supply. Noradrenaline produces a more favourable splanchnic haemodynainic profile than dopamine,3 with increased gastric intramucosal pH (pHi), indicating improved regional oxygen tissue utilization. Dopamine, while increasing splanchnic blood flow, decreases pHi, indicating an uncomrn sated increase in regional oxygen requirements. Clinical presentation Sepsis, severe sepsis and septic shock (Table 61.1) are stages in a spectnlm of pathophysiological disturbances in the infected patient. Sepsis is common and can present many faces. Many septic patients are referred to the ICU with such labels as cardiogenic shock, pulmonary embolism, hypovolaemic shock, profound hypothermia and haemolytic uraemic synd rome. Conversely, there are many causes of syst emic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) other than sepsis. However, as sepsis requires specific therapy, the patient with signs consistent with sepsis should be considered as being infected until proven otherwise. Sepsis may present with a wide spectrum of manifestations. Body temperature may be normal, increased or decreased. Tachycardia and tachypnoea are common. A leukocytosis and increased numbers of immature (band) forms is usual, although leukop enia may be seen. Other signs and symptoms may relate to the site of infection (e.g. productive cough, dyspnoea, cyanosis and pleuritic pain with pneumon ia). Other features often relate to organ dysfunction (MODS), e.g. encephalopathy, renal impairment and gut dysfunction. Coagulopathy is occasionally prese nt. Glucose intolerance is common, although if hepatic dysfunction is present, hypoglycaemia may occasionally occur. The picture of a septic patient with warm skin, bounding pulses and a hvperdvnamic circulation is nut alsv;o present. ITx pu1eniun. ascunstritin and peripheral cyanosis (i.e. cold shock) may present if the patient is hypovolaemic, has pre-existing myocardial dysfunction, or has been referred late. Management Septic shock has a high mortality rate and efforts should be made to diagnose and treat sepsis

before shock occurs. As with any critically ill patient, these management principles are important: 1 initial assessment with resuscitation; 2 steps to ensure adequate oxygen delivery to meet oxygen demands (Table 61.3): 3 attempts to diagnose and eradicate the cause of illness. General measures Oxygenation and ventilation Hypoxaemia is common. If oxygen by mask is inadequate, then continuous positive airway pressure (CPAP) by mask may be employed. Where respirat ory failure is severe, endotracheal intubation and either CPAP or mechanical ventilatory support is necessary. An adequate haemoglobin level must also be maintained. Table 61.3 General measures in septic shock Administer oxygen, ventilatory support if indicated Basic clinical monitoring ECO, systemic arterial pressure (SAP) Central venous pressure (CVP) Pulmonary artery pressure (PAP) Pulmonary capillary wedge pressure (PCWP) Cardiac output (CO) Oxygen delivery (Do2) Temperature, urine output Chest X-ray Basic laboratory monitoring Arterial blood gas/acid-base Lactate Electrolytes, creatinine Blood sugar, haemoglobin Platelet and white blood cell count INR Liver function tests ECG = Electrocardiogram; INR = intemational normalized ratio. 530

61 Severe sepsis Clinical monitoring and intervention A central venous (preferably multi-lumen) and arter ial line and a urethral catheter are inserted. Heart nile. rhythm. n1emn rterm:ml pressure MAP. central venous pressure (CVP) and urine output are cont inuously monitored. Haemodynamic manipulation There is no consensus view on the correct haemodyn amic goals in septic shock, but a plan of haemodyn amic management is needed. Tachycardia is comm on in sepsis, so increasing heart rate is usually not an issue. Volume loading is usually with colloids, such as 5% albumin or Haemaccel (12 I) followed by normal saline. If MAP is inadequate (i.e. <65 8OmmHg or 8.6lO.6kPa) despite attaining a CVP of 15cm H20 (l0l2mmHg or l.3 I.6kPa),an inotrope infusion should be started usually adrenal ine initially, at 5 i.g/kg per mm and varying the dose as necessary. A pulmonary artery catheter should be inserted to monitor pulmonary capillary wedge press ure (PCWP), CI and SVRI, if inotropes are started. Volume loading is continued if necessary, to a PCWP of l2mmHg (1.6kPa). A PCWP of l0 l2mmHg (1.31.6 kPa) is associated with peak left ventricular stroke work and CI in septic patients.32 Sustained PCWP over 12 mmHg (1.6 kPa) may lead to pulmon ary oedema due to increased pulmonary capillary leak. An adequate MAP (i.e. 658OmmHg or 8.6lO.6kPa) and CI (>4.0) should be aimed for. Blood pressure is important; blood flow to most organs is pressure-dependent, and autoregulation is probably lost with the profound vasodilatation in septic shock. Arterial pressure and SVRI have been shown to correlate directly with survival in septic shock.3334 Noradrenaline vasopressor is reported to improve SVRI, blood pressure, regional blood flow, oxygen extraction and urine output.3135 Haemoglob in concentration should be maintained above 10 g/dl for adequate Do2. Haemodynamic interventions should avoid: 1 overdriving the heart with excessive catecholam ines which are cardiotoxic, arrhythmogenic and increase oxygen requirements; 2 using inappropriate agents, e.g. dobutamine (an inodilator) instead of noradrenaline in a patient with profoundly low SVRI. Afterload reduction to improve right ventricular function is a consideration in pulmonary hypert ension, which is associated with a high mortality)8 Vasodilators such as hydralazine, sodium nitropruss ide and prostacyclin lower PVR and also SVRI, and are prone to cause

hypotension and increase pulmon ary shunt. NO, by inhalation, is a selective pulmon ary vasodilator,36 but its use is still experimental. Urine output A urine output over 0.7 mllkg per h should be maintained. If severe oliguria persists despite the above measures. IV mannitol (0.3 e/ke) and/or TV frusemide 250500mg is commonly given. These agents may increase renal blood flow and promote diuresis. However, frusemide can precipitate hypot ension (by causing vasodilatation) and may worsen toxic nephropathy. Chest X-ray An early erect chest X-ray may show evidence of raised pulmonary venous pressure. In severe sepsis, considerable tachypnoea and hypoxaemia may exist despite a deceptively normal-looking chest film. Laboratory monitoring Increases in blood lactate suggest severe tissue hypoxaemia, and may indicate an advanced stage of decompensation. However, in severe sepsis, lactate may be increased by other mechanisms. For example, increased circulating catecholamines promote glycoly sis (by stimulating cyclic adenosine monophosphate to augment glycogen phosphorylase). The increased concentration of pyruvate so produced leads to increased production of lactate. Conversely, in maln ourished patients with low glycogep stores, the increase in lactate for a given level of hypoxia may be less. Hence, lactate may be an insensitive marker of tissue hypoxia.37 Controversies in haemodynamic management It has been suggested that the optimal goals of therapy in septic patients may be supranormal values (Table Using these goals, better survival has been reported, and pathological supply depende ncy was demonstrated (i.e. increases in Do2 were reflected by increases in Vo2).404 However, these recommendations have been challenged. Other worke rs have shown no differences in outcome.42-47 In one study, target Vo2 values could not be attained in some patients despite achieving target CI and Do2,48 Table 61.4 Supranormal values (normal values in brackets) Cardiac index > 4.5 11mm per m2 (2.53.5) Do2 > 600 mllmin per m2 (400700) 1/02> 170 mI/mm per m2 (130150) PCWP = l8mmHg; 2.4kPa (l5mmHg; 2.OkPa) Severe trauma and septic patients may require greater

increases39 Do2 = Oxygen delivery; 1/02 = oxygen consumption; PCWP = pulmonary capillary wedge pressure. 531 Infections and immune disorders suggesting that Increasing Do, does not affect the inability of tissues to extract or utilize oxygen. Future efforts should be directed away from global values of Cl. Do. and Vo. towards monitors and markers of individual olgan o\ygcnanon and function. Currenti). pHi is of much interest. It is more likely to benefit patients at risk of developing shock rather than those already in shock,49 but further evaluation of its role is necessary. Dobutamine has been the most common inotropic agent used in reported studies. The possibility exists that dobutamine may have worsened peripheral maldistribution of blood in those patients. Also, aggressive use of dobutamine to achieve supranormal goals may have been detrimental.47 In clinical practice, the choice of inotrope should be influenced by the initial MAP, CI and SVRI following volume loading, and by the clinical response. Specific measures Blood cultures Blood cultures are taken repeatedly before antibiotics are given. A set of cultures consists of six bottles three aerobic and three anaerobic each bottle receiving 5 ml of blood. Gram stain and culture Appropriate specimens of sputum, urine, peritoneal dialysis fluid, cerebrospinal fluid (CSF) and pus should be examined microscopically, Gram-stained and cultured. Specimens for specific antigens and serology Specific serological tests should be requested if appropriate. Similarly, a search for specific antigens (e.g. pneumococcal and meningococcal) may be relevant, especially in CSF specimens of patients with suspected bacterial meningitis who were previously given antibiotics. Antibiotics

Adequate antibiotics are given following collection of blood and specimens for cultures. The regimen is initially a best guess based on: 1 the possible site of infection; 2 whether the infection was acquired outside or within the hospital; 3 the age of the patient; 4 any history of hypersensitivity; 5 renal function; 6 whether previous antibiotics have been given. The regimen may need to be changed once the organism and sensitivities are known (see Chapter 64). Surgical drainage Surgical debridement or drainage of in ection source is vital. If intra-abdominal abscesses are left undrained. rnortalii approaches lOO.50 Locating sources ol infection can prove diflicult and frustrati ng. In suspected intra-abdominal sepsis, plain abdominal X-rays, ultrasonography, computed tomography (CT) scan, gallium 67 citrate scan and indium 111labelled leukocytes may be helpful,5 but may also be misleading. The choice of investigation is guided by availability, expertise and the clinical situation. If intra-abdominal sepsis is strongly susp ected despite negative clinical findings, exploratory laparotomy should be undertaken.52 Direct percutan eous drainage may be attempted in selected cases, when a definite abscess is located by ultrasonography or CT scan. Severe diffuse peritonitis has a high mortality, and aggressive forms of therapy have been thed. Howe ver, radical peritoneal debridement or postoperative continuous pentoneal lavage offers no benefit. Repeated laparotomies also confer poor results.53 Electively staged laparotomies and open management of the abdomen (possibly with use of a mesh zipper)54 are also proposed.5556 Advantages claimed for open management include maximal drainage, ease of repeated debridement and lowered intra-abdominal pressure.55 This method should be resrved for severe cases; mortality remains high and its superiority remains unestablished.56 Measures for specific infections Additional measures are relevant to the following infections. Gas gangrene Massive doses of crystalline penicillin are given with clindamycin, and urgent radical

debridement or amputation is undertaken. Hyperbaric oxygen may be beneficial, but prospective evidence to support its use is lacking (see Chapter 63). Systemic candidiasis This is usually seen in immunodepressed patients receiving antibiotics. As fungaemia may arise by translocation from the bowel,57 ICU patients on broad-spectrum antibiotics should be given prophyl actic oral or nasogastric nystatin suspension or amphotericin B. In suspected systemic candidiasis, ophthalmitis, osteomyelitjs, arthritis, myocarditis, meningitis and macronodular skin lesions must be excluded. Established agents for treating Candida infections are amphotericin B, flucytosine and flucon azole58 (see Chapter 64). Necrotizing fasciitis Necrotizing fasciitis is a fulminant infection of subcutaneous tissues with extensive undermining of 532 Hypercatabolism skin, usually occurring on the extremities, perineum and abdominal wall. Patients with cirrhosis, diabetes and immunocompromised conditions are more likely victims. Infecting organisms are usually enteric howel oreumms. thtu pp.. LmLlp A streptococci. and occasionally Staphylococcus aureus. Exteimive early debridement and antibiotic therapy are the essential components of therapy (see Chapter 63). Meningococcal meningitis and meningococcaemia These fulminant conditions have a high mortality. Antibiotics must be given immediately; ceftriaxone 12g 12-hourly or cefotaxime I2g 68-hourly is usually appropriate. Dexamethasone 0.15 mg/kg 6-hourly for 2 days should be started before antib iotics in children, but not for adults. Lumbar puncture will be unsafe if coagulopathy is present (see Chapter46). Complications of sepsis Metabolic acidosis

This is commonly present because of lactic acidaemia from anaerobic metabolism. Measures to improve Do2 will usually reverse this. However, severe metabolic acidosis worsens myocardial depression and increases PVR and venoconstriction. Use of bicarbonate remains controversial.59 Hyperglycaemia Glucose intolerance is commonly precipitated by severe sepsis, and aggravated by steroids and hypert onic glucose infusions. A low-dose insulin infusion may be necessary. Hypoglycaemia may occasionally be seen, especially in the very young and those with severe hepatic dysfunction. Coagulopathy Mild to severe disseminated intravascular coagulation may occur in septic shock. Platelets, fresh frozen plasma and other factors are given if necessary (see Chapter 89). Vitamin K and folate are routinely given if no contraindication exists. Gastrointestinal bleeding Antacids, H2-receptor blockers and sucralfate are effective in reducing GIT bleeding in sepsis (see Chapter 35). Sucralfate has a minimal effect on intragastric pH and has antimicrobial properties. Whether it is associated with less gastric colonization and nosocomial pneumonia in ventilated patients is debatable.606 Severe sepsis is associated with a hypercatabolic state. Muscle wasting can be profound. Negative nitrogen balance can be minimized by providing lequiiie nutri jonul support. Multiple organ dysfunction and failure Multiple organ dysfunction and/or failure is a feature of severe sepsis and septic shock. Virtually any organ may be involved (see Chapter 85). Novel, experimental and controversial therapies Antiendotoxin antibodies Antiendotoxin antibodies have not improved survival in several clinical trials.62 These included polyclonal antiendotoxin anticore antibodies against E. coli J5,6268 and monoclonal antiendotoxin antibodies ES (Xoma)697 and HA-IA (Centocor).7172 The CHESS HA-lA study was stopped because mortality in the treated group exceeded that of patients given plac ebo.73 At present, agents with a higher binding affinity with endotoxin than antibodies previously studied are being developed.62 Anticytokine therapies

Cytokines are small proteins produced by macrop hages and other immune cells, and are primary mediators of inflammation with an important role in regulating host defences. Levels of TNE IL-I and IL- 6 are increased in septic shock.74 Anticytokine therapy is thus based on the assumption that suppress ion of an exaggerated inflammatory response is beneficial. However, anti-TNF antibodies and soluble TNF receptors did not affect 28-day mortality in a multicentre trial.62 Although increasing doses of ILI ra were reported to relate to improved survival,75 no difference in mortality was shown in a larger IL-lra trial.76 Modifying neutrophil function Experimental studies of monoclonal antibodies to inhibit neutrophil adhesion have shown varying beneficial and adverse effects.Th78 Granulocyte colo ny-stimulating factor (GCSF) has been shown to be beneficial in animal experiments.7980 However, evid ence of clinical benefit is lacking. Nitric oxide NO has important roles in neurotransmission, regulat ion of vascular tone, platelet inhibition and leukocyte adhesion, with antitumour and bactericidal effects in higher concentrations. Blocking its production in Infections and immune disorders sepsis is rationalized by its implications in myoc ardial depression23 and vasoplegia.8 NO synthase inhibitors have been used in sepsis to treat hypotens ion.8284 However, improved survival has vet to be shov n convilkillg1. Indeed, ann-NO therap) could well be harmful. Steroids The use of high-dose steroids (e.g. methyiprednisol one 30 mg/kg and dexamethasone 6 mg/kg) does not improve overall survival in septic shock.85 Moreover, steroid treatment is associated with more deaths related to secondary infection.8687 Use of steroids cannot be recommended except for bacterial meningit is in children88 and Pneumocystis pneumonia.89 Prostaglandins Prostaglandins participate in the pathophysiology of septic shock. Indomethacin and ibuprofen, prostag landin cyclooxygenase inhibitors, have not been shown to improve human survival in sepsis.909 Prostacyclin (prostaglandin; PGI2) is a vasodilator; it antagonizes thromboxane A2 and inhibits platelet aggregation, and is reported to improve peripheral oxygen utilization in critically ill patients,2 but evidence of benefits in sepsis is lacking. Alprostadil (prostaglandin E,) produced no improvement in survival in patients with acute

respiratory distress syndrome (ARDS).93 Naloxone Endogenous opioid peptides derived from 3-lipo- tropin are released in septic shock and other stress states. Despite earlier encouraging reports, naloxone, an opioid receptor blocker, offers no real therapeutic benefits in septic shockY Thyrotrophin-releaSing hormone (TRH) TRH, like naloxone, opposes many opioid-mediated actions. Although it has been studied in experimental shock, its clinical role is unknown. Phospholipase A2 inhibitors Endotoxin and bacterial products activate cell phosp holipases to liberate arachidonic acid (and initiate synthesis of leukotrienes, prostaglandins and thromb oxanes) and, with phospholipase A2, activate PAF. Drugs that inhibit phospholipase Aa have been shown to prevent lung injury in animals,996 but usefulness in human sepsis is unknown. Antioxidants Free radical production is increased in sepsis and produces a toxic effect by interacting with cell structure, processes or genetic activity. Endogenous protective antioxidants include vitamins C, E, B carotene, sulphydryl group donors (e.g. glutathione), proteins with sulphydryl group and enzymes (e.g. superoxide disniutase and catalasel Encouraging results ha e been repoited in ARDS, and ant,ox,dants may have potential benefits in sepsis,97 but pros pective clinical trials are required. Ketoconazole Ketoconazole, a thromboxane A2 synthetase inhibitor, has been shown to reduce the incidence of ARDS9899 and mortality in septic patients.98 Ketoconazole also inhibits the synthesis of leukotrienes and interacts with other mediators such as IL-I and TNF. Pentoxifylline Pentoxifylline is a phosphodiesterase inhibitor, thus blocking chemotaxis and activation of neutrophils. It reduces the formation of TNF and increases survival in murine endotoxic shock, and has been safely given to patients with ARDS. Further investigation of this agent is needed. Haemofiltration Haemofiltration can remove certain circulating cytok ines from septic patients,23 and benefits have been suggested.l03_l05 In particular, plasma exchange has been used in the treatment of meningococcal infection.06 However, haemofiltration will not affect cytokines

that are fixed to cells, and many mediators of sepsis are cell-associated. Prospective controlled clinical trials on dialytic therapies for sepsis are required.7 Prognosis Mortality increases with increasing severity score (e.g. APACHE II), number of dysfunctionallfailed organs and duration of such failure. 108.109 Several factors influence the prognosis in bacteraemia and fungaemia in tsdults:0.W source of infection, where acquired, blood pressure, organism isolated, body temperature, age and predisposing factors. Survival is improved by appropriate use of antibiotics and surgical drainage (where applicable). The ability to maintain an increased CI, Do2 and Vo2 is associated with better pronosis.33 Pulmonary hypertension is an adverse factor. 8 Peripheral vascular failure may be a major haemodynamic determinant of mortality, as survivors of septic shock are more able to augment svlu.34 Prevention of sepsis in ICUs Four main facets are important: reducing available routes of infection; preventing transfer of pathogenic organisms and development of resistant strains; 61 Severe sepsis improving host defences; and reducing risk of endogenous infection from the gut. Reducing available routes of infection All invasive cannulae and tubes should be removed when no longer necessary. Subclavian central lines have lower rates of infection than femoral sites and are preferred.2 Triplelumen central venous cathe ters induce a higher sepsis rate than single-lumen catheters. Preventing transfer of pathogenic organisms and development of resistant strains Hand-washing must be performed by staff members before and after attending each patient. All invasive procedures, including endotracheal suctioning, must be done aseptically. If prophylactic antibiotics are employed, narrow-spectrum agents should be used with a limited duration. Indiscriminate use of antib iotics leads to serious outbreaks of infection within the ICU (see Chapter 64). Improving host defences Potentially valuable measures include:

1 nutritional repletion; 2 surgery, e.g. drainage, control of haemorrhage and resection of colonic cancer; 3 active immunization, e.g. pneumococcal, Haem ophilus influenzae type B,5 and meningoc occal6 vaccination of splenectomized patients; tetanus and hepatitis B vaccines; 4 passive immunization (e.g. human antitetanus, and pneumococcal and hepatitis B globulin); 5 granulocyte transfusion in the profoundly leuk openic patient. Immunostimulation with agents such as levamisole, bacillus Calmette-Gurin (BCG) and Corynebacter ium parvum may be useless or even dangerous.9 Infusions of fibronectin, cryoprecipitate, fresh frozen plasma, -y-globulin and transfer factor are of unprov en benefit. Reducing risk of endogenous infection from the gut Early enteral feeding Early enteral feeding can reduce bacterial and endotoxjn translocation from the gut, and infection rates in animals and humans.7 Larger studies are needed on outcome and influence of food composition. Improving gut blood flow Bacteraemia commonly occurs in patients with haemo rrhagtc shock,8 Decreased intestinal blood flow may be important in bacterial gut translocation. Early adequate resuscitation aims to improve gut blood flow. Selective oropharyngeal and gastrointestinal decontamination Organisms commonly causing infections in the compromised patient may be communityacquired (e.g. Streptococcus pneumoniae, Haemophilus influe nzae, Branhamella catarrhalis, E. coli, Staphyloc occus aureus and Candida albicans) or nosocomial (hospital/ICU-acquired, e.g. Kiebsiella, Proteus, Morganella, Enterobacter, Citrobacter, Serratia, Acin etobacter and Pseudomonas).9 Normal indigenous flora of the throat and alimentary tract are anaerobic (>99%), and are rarely involved in infection. Select ive decontamination aims to prevent or eradicate colonization by community/hospital-acquired pathog ens, and preserve protective normal flora. Community flora are eradicated by short-term parenteral antibiotics. Therapy against hospital- acquired flora is by topical application of non- absorbable antimicrobial agents (Table 61.5). 120 Init ial repots20-22 and meta-analysis of available studies2324 are favourable, but outcome has remained unchanged.25

Table 61.5 A regimen for oropharyngeal and gastrointestinal decontamination Systemic antibiotic (first 4 days) cefotaxime IV 50100mg/kg per day in four divided doses Topical antimicrobial (whole of ICU stay) Oropharyngeal: Cleanse mouth with 0.1% chlorhexidine aqueous solution Apply carboxymethylcellulose (Orabase) containing: 2% polymyxin E 2% tobramycin 2% amphotericin B A small quantity on a gloved finger is applied to buccal mucosa four times a day. Gastrointestinal: 100mg polymyxin E 80mg tobramycin 500mg amphotericin B as a 10-mi mixture, delivered four times a day via a nasogastric tube 535