Introduction: Acute inflammation is the principal mechanism by which living tissues respond to injury. The purpose is to neutralise the injurious agent, to remove damaged or necrotic tissue and to restore the tissue to useful function. The central feature is formation of an inflammatory exudate with three principal components: serum, leucocytes (predominantly neutrophils) and fibrinogen.

Formation of inflammatory exudate involves local vascular changes collectively responsible for the four ‘cardinal signs of Celsus’—rubor (redness), tumor (swelling), calor (heat) and dolor (pain)—as well as loss of function. These vascular phenomena are described in Figure 3.1. The outcomes of acute inflammation are summarised in Figure 3.2.

The chronic state: (see Chronic inflammation, p. 37)

The essence of managing any abscess is to establish complete drainage, usually by incision or aspiration. Any residual necrotic or foreign material needs to be eliminated by curettage or excision. If drainage of an abscess does not eliminate the injurious agent, the neutrophil response persists and pus continues to be formed, resulting in a chronic abscess.

Antibiotics and abscesses: If appropriate antibiotics are given early enough, organisms can be eliminated before abscess formation. In surgical operations with a particular risk of infection, therefore, prophylactic antibiotics dramatically reduce abscess formation and other infective complications. However, once an abscess has fully formed, antibiotics seldom effect a cure because pus and necrotic material remain and the drug cannot gain access to the bacteria within. Nevertheless, antibiotics may halt expansion or even sterilise the pus; the residual sterile abscess is known as an antibioma.

Organisation and repair: The most common sequel to acute inflammation is organisation, in which dead tissue is removed by phagocytosis and the defect filled by vascular connective tissue known as granulation tissue. This tissue is gradually ‘repaired’ to form a fibrous scar. Sometimes the original tissue regenerates, i.e. rebuilds its specialised cells and structure.

Healing by primary intention: The simplest example of organisation and repair is healing of an uncomplicated skin incision (see Fig. 3.4). There is no necrotic tissue and the wound margins are brought into apposition with sutures. An acute inflammatory response develops in the vicinity of the incision, and by the third day granulation tissue bridges the dermal defect. In the meantime, epithelium proliferating rapidly from the wound edges restores the epidermis. Fibroblasts invade the granulation tissue, laying down collagen so the repair is strong enough for suture removal after 5–10 days. The scar is still red but blood vessels gradually regress and it becomes a pale linear scar within a few months. This is known as healing by primary intention.

Healing by secondary intention: If tissue loss prevents the wound edges from coming together, healing has to bridge the defect, which is initially filled with blood clot. This later becomes infiltrated by vascular granulation tissue from the healthy wound base. Inflammatory exudate solidifies, forming a protective scab. Fibroblasts invade and lay down collagen in the extracellular spaces; after about a week, some fibroblasts differentiate into myofibroblasts and contraction of their myofibrils eventually shrinks the wound defect by 40–80%, beginning about 2 weeks after the injury. Over the weeks and months, blood vessels regress and more collagen is formed, leaving a relatively avascular scar; gradual contraction of the mature collagen (cicatrisation), combined with wound contraction, ensures the final scar is much smaller than the original defect. The epidermal defect is gradually bridged by epithelial proliferation from the wound margins. Epithelial cells slide over each other beneath the edges of the scab on the granulation tissue surface and the scab is eventually shed. This whole process is known as healing by secondary intention (see Fig. 3.4).

Factors impairing wound healing: The rate and success of wound healing may be impaired by a variety of local, regional and systemic factors (see Fig. 3.5).

• Infected foreign bodies are probably the most common cause in modern surgical practice. Foreign bodies implanted deliberately may become infected (e.g. synthetic mesh for inguinal hernia repair, prosthetic hip joint); others become embedded during trauma (e.g. glass fragments)

• Dead (necrotic) tissue can act as a foreign body, forming a nidus for infection. For example, diabetes may be complicated by deep foot infections with necrosis of tendon and bone leading to chronic abscesses and ulcers. Hairs deeply implanted in the natal cleft skin may cause a pilonidal sinus or abscess. An infected dead tooth or root fragment may intermittently discharge via an associated ‘gum boil’ (see Fig. 3.6). Chronic osteomyelitis is associated with remnants of dead bone known as sequestra

• Deep abscesses. A chronic abscess can arise without a foreign body if the acute abscess is so deep as to prevent spontaneous drainage. The best example is a subphrenic abscess

Environment: Patient areas in hospitals must be clean and free from contaminating bacteria, including MRSA, especially where invasive procedures occur such as operating theatres and high-dependency units. Special precautions are taken in theatres (see Ch. 10, p. 124).

Staff: Staff must be vaccinated against hepatitis B. HIV-positive individuals should not undertake invasive procedures. Open wounds must be securely covered and staff with infective skin lesions should avoid patient contact. Universal blood and body fluid precautions should be taken to prevent viral transmission (see below) and guidelines followed for dealing with needle-stick injuries. Risk of MRSA and other infections can be drastically reduced by the simple measures such as washing hands with alcohol-based gel between every patient contact.

Patients: Bacterial swabs should be taken for MRSA from patients before admitting them to hospital and MRSA-positive patients should receive topical eradication therapy and have follow-up bacterial screening cultures to assess MRSA status before major surgery, e.g. hip replacements, arterial grafts. Patients known to have transmissible infections or to be carriers, e.g. of MRSA, should be nursed in isolation. Surgery should ideally be deferred on patients with acute respiratory or urinary tract infections.

Procedures: Equipment—including instruments, needles, theatre gowns and drapes—must be sterile, in secure packaging or as single-use disposable items.

Hepatitis B vaccination: Staff directly involved in patient care should be vaccinated against hepatitis B. Hepatitis B serology should be checked 2 months after completion of vaccination. Around 5% of healthy young people fail to seroconvert and should be revaccinated. Half of these will seroconvert and the remainder are genetic non-responders.

Needle-stick and other penetrating injuries: Sharps injury, especially from a contaminated hollow needle (needle-stick injury), may lead to transmission of infection if the patient carries a blood-borne virus. Such injuries are capable of transmitting hepatitis B and C but the risk for HIV is much lower because the viral concentration in HIV-positive fluids is much lower and the volume transmitted is small.

Needle-stick injury is common but is largely avoidable: resheathing of used needles causes about 40% of needle-stick injuries and should be avoided. Venepuncture is a high-risk procedure and should be performed with caution. Needles, scalpel blades and other disposable instruments contaminated with blood should be handled with care and disposed of immediately into special plastic ‘sharps’ containers.

Viral infection following sharps injury: If a definite sharps injury has occurred that involves blood being transmitted from an infected person, the risk of hepatitis B infection to the recipient is about 25%. For hepatitis C the risk is 2% and for HIV 0.5%. There is also a very high risk after sharps injury in a recreational environment (e.g. needles left on the beach by intravenous drug users) since hepatitis B and HIV survive well in warm, moist conditions, especially in serum and tissue debris. Thus all sharps injuries should be treated with the utmost concern. A recommended protocol is shown in Box 3.1.

After a significant exposure to HIV, antiretroviral drugs should be given promptly for post-exposure prophylaxis, ideally within 24 hours. A combination of antiretroviral drugs is given for 4 weeks. Side-effects are often very unpleasant and include bone marrow suppression, nausea and other gastrointestinal symptoms, and headache. For health care workers exposed to hepatitis C, no vaccination or preventative treatment can yet be recommended. Guidelines for post-exposure management are to enable early identification of infection and specialist referral.

Removal of infected foci: A poorly vascularised infected area is effectively isolated from humoral and cellular defence mechanisms and from circulating antibiotics. Retained infected material may overactivate cytokine mechanisms and thus precipitate systemic sepsis. A vital first step is to remove infected necrotic tissue and drain collections of pus. This applies even if the patient appears too ill for operation because the very ill patient may recover dramatically after this type of surgery. Common examples include draining abscesses, amputating infected necrotic limbs, removing infected foreign bodies (e.g. cannulae, prostheses, trauma debris) and draining the infected contents of hollow viscera such as bile ducts, kidneys and ureters.

Antibiotic therapy (see Table 3.1):

Pathophysiology: Staphylococci are Gram-positive cocci, and Staph. aureus is the main pathogenic species. It is part of normal human bacterial flora, with about 30% of the population being nasal carriers and 10% carrying it on perineal skin. Staph. aureus typically produces pustules, boils, breast abscesses, wound infections and osteomyelitis. Its virulence is partly due to the enzymes and toxins it produces. A few patients harbour virulent strains that produce the toxic shock syndrome toxin (TSST-1). Infection produces toxic shock syndrome with serious systemic effects such as hypotension, shock and multi-organ failure. Staph. epidermidis (formerly Staph. albus), a coagulase-negative staphylococcus, is a universal skin commensal rarely causing significant infection and meriting antibiotics only when it causes infections of exogenous materials such as prosthetic implants and intravenous cannulae.

Some strains, including MRSA, can be passed from patient to patient on staff hands if care is not taken with hand washing after every patient contact.

Antibiotic sensitivities: Most strains were sensitive to penicillin but more than 85% are now resistant in family practice and hospital. Resistance is largely due to production of the enzyme beta-lactamase (also known as penicillinase). Most strains remain sensitive to a range of common antibiotics, e.g. flucloxacillin, erythromycin and some cephalosporins. Gentamicin is also active.

Pathophysiology: Streptococci are Gram-positive coccoid organisms first described in infected surgical wounds by Billroth in 1874. They are classified by their oxygen requirements into aerobic, anaerobic and microaerophilic and subdivided by their haemolysis patterns on blood agar culture plates. Alpha-haemolytic streptococci cause partial haemolysis with green discolouration; important pathogens include the viridans group and Strep. pneumoniae. Beta-haemolytic streptococci produce complete haemolysis and can be grouped serologically into Lancefield groups A to O. The important human pathogens are group A (Strep. pyogenes—of major surgical importance) and group B (Strep. agalactiae—a common cause of serious neonatal sepsis). Group C and G streptococci are occasional causes of cellulitis and bacteraemia. Microaerophilic streptococci such as Strep. milleri carry a group F antigen.

Streptococci of particular surgical significance:

Anaerobic streptococci: These are bowel commensals and may form part of the mixed flora in intraperitoneal abscesses or infections associated with necrotic tissue, e.g. diabetic foot ulcers.

Antibiotic sensitivities: Penicillin is the drug of choice for most streptococcal infections. In seriously ill patients, benzylpenicillin is given parenterally. For less serious infections in patients able to tolerate oral therapy, penicillin V (phenoxymethylpenicillin), ampicillin or amoxicillin are the drugs of choice. Many streptococci are also sensitive to macrolides (e.g. erythromycin, clarithromycin). Some pneumococci are now partially resistant to penicillin. Most infections, however, are still cleared with high-dose penicillin although meningitis needs alternative antibiotics such as ceftriaxone or vancomycin.

Pathophysiology: The enterococci are Gram-positive cocci closely related to streptococci. E. faecalis (formerly Strep. faecalis) is the most common species. Enterococci are part of the normal bowel flora and may cause infection where bowel has been opened or else infect urinary or genital tracts.

Antibiotic sensitivities: Penicillin, ampicillin, amoxicillin or vancomycin are used for enterococcal infections. In serious infections such as endocarditis, a combination of high-dose penicillin and gentamicin ensures bactericidal activity. The cephalosporins are all ineffective. In hospitals where broad-spectrum cephalosporins are used empirically for bowel-related infections or septicaemia, enterococci are a frequent cause of nosocomial (hospital-acquired) infection. Vancomycin-resistant enterococci (VRE) are now being found. They are usually low-grade pathogens infecting intravascular lines in transplant and haematology patients and on ICUs. VRE endocarditis is difficult to treat, but newer antibiotics linezolid, daptomycin and quinupristin/dalfopristin are active against most strains.

Pathophysiology: The Enterobacteriaceae are a large family of Gram-negative bacilli (rods) and usually make up about 1% of intestinal flora (see Table 3.2); they are known as coliforms and can be cultured under aerobic and anaerobic conditions and, like other bowel flora, grow in bile salt-containing media such as MacConkey or CLED agar; this helps identification.

Infections of surgical importance are usually opportunistic with the bacteria originating from the patient’s bowel. Infection results from direct contamination (perforated or surgically opened bowel), perineal spread (to nearby wounds or urinary tract) or haematogenous spread. These and other Gram-negative organisms contain the sugar lipopolysaccharide (LPS), a powerful stimulator of inflammation and macrophage production of TNF-alpha and interleukin-1 cytokines.

Escherichia coli is the most common pathogen of the group and causes many surgical infections, often in synergy with other bacteria. E. coli causes Gram-negative sepsis and about 80% of urinary tract infections. Coliform bronchopneumonia occasionally occurs in debilitated, immunosuppressed or seriously ill patients. Klebsiella, Enterobacter and Serratia are found more often in surgical bowel-related infections. Proteus is a common cause of urinary tract infections but occasionally causes other surgical infections, usually originating from the urinary tract.

Antibiotic sensitivities: Many coliforms are now resistant to ampicillin (and amoxicillin) and first-generation cephalosporins, e.g. cefalexin, but most are sensitive to second- and third-generation cephalosporins, e.g. cefuroxime, cefotaxime. Gentamicin is still a very effective and cheap agent. Many are sensitive to fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) but resistance is emerging. For prophylaxis in bowel and biliary tract surgery and for related local and systemic infections, gentamicin or an amoxicillin–clavulanate combination (co-amoxiclav) is recommended for its additional anaerobe activity. Antibiotic and beta-lactamase inhibitor combination antibiotics such as co-amoxiclav or piperacillin–tazobactam are very active against bowel flora with good activity against anaerobes. Anaerobes are the main colonisers of the bowel and often accompany Enterobacteriaceae in infections.

Resistant strains of Enterobacteriaceae are much more frequent in hospitals (often on ICUs) than in the community. They often cause urinary tract infection in catheterised patients after repeated courses of antibiotics. Multi-drug resistant strains of E. coli and Klebsiella spp. have emerged in hospitals all over the world since the 1980s. They produce enzymes (extended spectrum beta-lactamase enzymes or ESBL) that destroy second- and third-generation cephalosporins, and are often resistant to quinolones and most aminoglycosides. The only active antibiotics are the carbapenems (meropenem, imipenem, ertapenem) and amikacin. The carbapenems are very broad spectrum, but expensive and must be given parenterally. Hospital use is restricted to prevent development of resistance. The emergence of carbapenemase-producing Enterobacteriaceae (called KPC or NDM) is a growing problem as treatment is largely limited to old and toxic antibiotics such as colistin. Resistant bacteria have now spread around the world and pose the greatest current infection threat to patients in hospital.

‘Non-surgical’ Enterobacteriaceae: Other members of the family cause primary bowel infections. Salmonella typhi causes typhoid which may cause bowel perforations and Shigella causes bacillary dysentery. Rarely, Salmonella is incriminated in acute appendicitis and primary ‘mycotic’ aneurysms. An increasingly important cause of acute haemorrhagic colitis is E. coli O157:H7 and other verotoxin-producing E. coli. This is indistinguishable from acute haemorrhagic ulcerative colitis and should be sought bacteriologically in all cases. These strains have also caused large outbreaks of food-borne disease and produce a verotoxin (Shiga-like toxin) responsible for haemolytic uraemic syndrome (HUS) resulting in acute renal failure. Yersinia sometimes produces an acute ileal inflammation which may mimic acute appendicitis and has a similar appearance to Crohn’s disease at laparotomy. Campylobacter jejuni, the most common cause of food-borne infection, can also cause a pseudo-appendicitis by initiating terminal ileitis and mesenteric lymph node inflammation.

Pathophysiology: The main pathogen in this group of aerobic Gram-negative rods is Pseudomonas aeruginosa, an uncommon cause of surgical infection except in debilitated, hospitalised patients. It is found in a wide variety of habitats including soil, water, plants and animals, reflecting its predilection for moist environments. It is commonly found on hospital and cleaning equipment and even in chemical disinfectants and antiseptics. In about 10% of the population, Ps. aeruginosa is a normal intestinal commensal and is primarily an in-hospital (nosocomial) pathogen. The organism is resistant to many antibiotics and so tends to proliferate when other flora are suppressed by broad-spectrum antibiotics.

Pseudomonas is a common colonising organism in long-standing wounds such as compound fractures, chronic leg ulcers and indwelling urinary catheters but its presence is not always clinically significant. In wounds and ulcers, it can be recognised by its characteristic blue-green discharge. It colonises burns and may become pathogenic with extensive burns, giving rise to fatal sepsis. Pseudomonas infection can be serious in ophthalmic surgery and may lead to loss of the infected eye and is often responsible for chronic and recurrent external ear infections (otitis externa). Finally, Ps. aeruginosa may be responsible for hospital-acquired pneumonias in ventilated patients or for fatal systemic sepsis in terminally ill patients.

Antibiotic sensitivities: True infection must, as ever, be distinguished from colonisation where treatment is not indicated and would encourage development of resistance. Ps. aeruginosa is intrinsically resistant to most antibiotics; those that have activity include the aminoglycosides (gentamicin and tobramycin), some extended-spectrum beta-lactam antibiotics (ceftazidime or cefepime), the combination of piperacillin and tazobactam and the carbapenems (imipenem or meropenem). The quinolones, ciprofloxacin and ofloxacin, are the only orally effective anti-pseudomonal agents.

Antibiotic sensitivities: Most anaerobes are highly sensitive to metronidazole. Metronidazole can be given orally, intravenously or rectally, with the rectal route resulting in plasma levels equivalent to intravenous administration. Metronidazole is standard prophylaxis before appendicectomy and large bowel surgery, and has dramatically reduced peritoneal and wound infections. Other antibiotics with broad anaerobic activity are co-amoxiclav (Augmentin), piperacillin/tazobactam (Tazocin), the carbapenems (imipenem and meropenem) and chloramphenicol.

Pathophysiology: Bacteroides cause pyogenic infections after faecal contamination of the peritoneal cavity, along with other gut commensals, and occasionally cause sepsis in debilitated patients. Bacteroides were not identified as pathogens until the early 1970s because their strict anaerobic culture requirements were unrecognised. Indeed Bacteroides spp. were probably responsible for many so-called ‘sterile’ intra-abdominal abscesses. The importance of B. fragilis as a cause of surgical infection is probably still underestimated.

Gas gangrene: Gas gangrene results when Clostridium perfringens (formerly C. welchii) and other anaerobes (e.g. Bacteroides spp. and streptococci) proliferate in necrotic tissue, secreting powerful toxins. Toxins spread rapidly and destroy nearby tissues, generating gas which causes the characteristic sign of crepitus (‘crackling’) on palpation and the typical X-ray appearance (Fig. 3.8). Deep traumatic wounds involving muscle, and wounds contaminated with soil, clothes or faeces are most susceptible. The condition is very common in battle wounds—gas gangrene was responsible for vast numbers of deaths during the First World War.

In surgical practice, the highest risk of gas gangrene is in lower limb amputations for ischaemia (infection from the patient’s bowel) and in high-velocity gunshot wounds (from perforated bowel or by external contamination). Gas gangrene occasionally occurs in surgical wounds when ischaemic tissue is contaminated with bowel flora. The area of muscle necrosis may initially be small. Gas gangrene is recognised when the overlying skin turns black and spreads at an alarming rate. Within hours, necrosis rages along muscle planes. Later the skin breaks down and a thin, foul-smelling purulent exudate leaks out. Toxins are absorbed and cause rapid clinical deterioration and death within 24–48 hours unless the process can be halted by timely and vigorous intervention.

C. perfringens is very sensitive to benzylpenicillin which should be given prophylactically by injection as soon as possible after a traumatic injury involving muscle, or less than an hour before ischaemic limb amputation (metronidazole is suitable for patients allergic to penicillin). In the surgery of contaminated wounds, preventing clostridial infection requires meticulous excision of all necrotic tissue followed by packing of the wound rather than suturing. Further excisions are likely to be needed and delayed primary closure performed when risk of infection is over, a few days later.

Tetanus: Tetanus is caused by Clostridium tetani, which also infects dirty wounds. The entry wound may be minute, perhaps caused by a rose thorn or splinter. The organism produces an exotoxin with little local effect but, even in minute quantities, with powerful neuromuscular effects causing widespread muscular spasm. The first signs are often acute muscle spasms and neck stiffness or trismus (‘lockjaw’). If untreated, these progress to opisthotonus (arching of the back due to extensor spasm), generalised convulsions and eventually death from exhaustion and respiratory failure several days later.

Tetanus is now rare in developed countries because of immunisation with tetanus toxoid during childhood, followed by boosters at 10-year intervals. In the UK, boosters are no longer needed if an initial five-dose vaccination schedule has been completed. In Australia and New Zealand a single booster is recommended at age 45–50. In developed countries, the annual incidence of tetanus is about one per million and is most common following trivial gardening injuries in the elderly. If the immunisation status following a major contaminated injury is unknown, benzylpenicillin should be given plus passive immunisation with tetanus immune globulin. Treatment of established tetanus usually requires artificial ventilation with drug paralysis, antibiotics and passive immunisation. Mortality remains high, especially in the elderly.

Globally, tetanus after trauma remains a massive problem. In some developing countries, neonatal tetanus results from the practice of applying cow dung as a dressing to the umbilical stump.

Pseudomembranous colitis: Pseudomembranous colitis can be the most serious form of antibiotic-associated diarrhoea (see Ch. 12) and is caused by overgrowth of a toxigenic Clostridium difficile. The organism gets its name from the difficulty of growing it in culture. Infection produces a thick fibrinous ‘membrane’ on large intestinal mucosa, within which the organism proliferates. Its toxins cause a profound watery and sometimes bloody diarrhoea, leading to dehydration and electrolyte loss.

Pseudomembranous colitis may develop after only a single dose of any antibiotic. Cephalosporins and ciprofloxacin are now the most common cause. Diagnosis can be made by sigmoidoscopy and biopsy in the 50% of patients with left-sided colonic involvement. Cases of pseudomembranous infection are increasingly recognised in patients after total colectomy and C. difficile should be suspected in cases of large unexplained stoma output and rising white cell count. Diagnosis is best made by detecting the specific toxin in the stool and looking for a cytopathic effect on cells cultured in vitro. C. difficile can also be cultured from the stool. Although the organism is sensitive to penicillin, this fails to penetrate the pseudomembrane. Oral metronidazole is usually effective but takes at least 2 days before clinical response is observed. Relapses are common in the elderly and oral vancomycin, which is not absorbed from the GI tract, can be employed or when metronidazole fails. Oral vancomycin should also be used if severe disease is suspected; the intravenous formulation can be given by rectal tube in patients unable to take oral treatment, especially on intensive care units. A new antibiotic, fidaxomicin, has recently been licensed for C. difficile infection and appears to have a lower relapse rate than traditional treatment.

Classification of HIV infections: The human immunodeficiency virus causes a chronic infection that usually progresses to the acquired immune deficiency syndrome (AIDS) over 7 or more years. The illness evolves through several stages or groups, classified by the US Centers for Disease Control, in 1986, as:

The use of combinations of antiretroviral drugs (‘high activity antiretroviral therapy’) has dramatically affected the natural history, with a large sustained drop in mortality from opportunistic infections.

Hepatitis A: Hepatitis A is transmitted by the faecal–oral route and has an incubation period of 2–6 weeks. It rarely causes fulminating disease and never leads to chronic hepatitis or cirrhosis. Its only surgical importance is in the differential diagnosis of jaundice. A vaccine for hepatitis A is available.

Hepatitis B: Hepatitis B is transmitted by blood or body fluids, including sexual intercourse, or from mother to fetus or baby (termed vertical transmission). Incubation is 6 weeks to 6 months. Hepatitis B infection leads to chronic hepatitis and cirrhosis in 5–10%; this variety of cirrhosis commonly progresses to hepatocellular carcinoma (the most common cause world-wide). Hepatitis B is preventable by vaccination and this is indicated for neonates of mothers who carry the virus, all health care workers and people living in high-risk areas.

Exposure to hepatitis B virus has several possible outcomes:

Hepatitis C: Hepatitis C is transmitted via the same routes as hepatitis B but sexual transmission is believed to be less common. The incubation period is approximately 2 months. Chronic liver disease develops in a higher proportion of cases (30–50%) but is often of low grade. Hepatitis C is also an important cause of hepatocellular carcinoma world-wide.

Serological diagnosis is troublesome because HCV antibody tests often give false positives. Seroconversion occurs late, often weeks to months after the acute illness. Definitive diagnosis is made by detecting hepatitis C RNA in serum. As in hepatitis B, viral load assays are used to monitor response to therapy and infectivity, and treatment with interferon and ribavirin has also been partially successful. In most cases a positive hepatitis C antibody test is likely to mean continuing infection.

Hepatitis D: This is a defective virus that requires hepatitis B surface antigen for full expression; it occurs only as a co-infection with hepatitis B and can be prevented by vaccination for hepatitis B.

Hepatitis E: Hepatitis E is transmitted by the faecal–oral route and is usually self-limiting.

Pathophysiology of SIRS and MODS: SIRS involves widespread changes, including inflammatory cell activation leading to cytokine release, endothelial injury, disordered haemodynamics and impaired tissue oxygen extraction. It thus represents grossly exaggerated activation of innate immune responses intended as host defences. An unregulated release of inflammatory mediators causes widespread microvascular, haemodynamic and mitochondrial changes that eventually lead to organ failure.

Following initial tissue injury, a local inflammatory response occurs with cytokine induction (see Immunity at the start of this chapter). The response to this is mobilisation of inflammatory cells including macrophages and neutrophils which diapedese into the tissues. In addition, cytokines provoke systemic elements of inflammation, including activation of endothelium, the complement system and blood coagulation, amplifying the primary inflammatory response. This sequence is part of the normal and appropriate inflammatory response. However, if the injury is severe or persistent, the local reaction may extend excessively into the systemic circulation producing a systemic inflammatory response, or if initiated by infection, the sepsis syndrome.

Mediators of SIRS and MODS: SIRS and MODS involve complex interactions of endogenous and sometimes exogenous mediators. A range of cytokines is released from activated macrophages and from endothelial and other reticulo-endothelial cells. The suite of cytokines released depends on the nature of the provoking agent and is governed by the specific type of Toll-like receptor that recognises the aggressor. Cytokines released include tumour necrosis factor-alpha (TNF-alpha), the interleukins (particularly IL1 but also IL2, IL6) and platelet activating factor. Pharmacological attempts to suppress excess cytokine responses have thus far been ineffective.

Sepsis: The classic septic response, with a hyperdynamic circulation, systemic signs of inflammation and disrupted intermediary metabolism, can be induced in healthy volunteers by injecting lipopolysaccharide (from the cell walls of Gram-negative bacteria) or the cytokines TNF-alpha or IL1. In Gram-negative sepsis, the lipopolysaccharide component of the organisms powerfully activates Toll-like receptors on dendritic cells and hence the whole inflammatory cascade. This results in endothelial activation which increases vascular permeability and neutrophil–endothelial interaction. The final common pathway may involve activated neutrophils migrating into the interstitial space of the affected organ and tissue hypoxia. In sepsis, these and other circulating factors working in synergy bring about the devastating effects of MODS.

• Inducing excessive release of endogenous cytokines

• Disrupting oxygen delivery to the tissues

• Impairing intestinal barrier function allowing translocation of intestinal bacteria and endotoxin to the portal and systemic circulations

• Damaging the reticulo-endothelial system

Infection: The infection source that leads to MODS may be acquired (e.g. intra-abdominal abscess) or endogenous, i.e. from the patient’s bowel. Local infection, especially with Gram-negative bacteria, stimulates the release of inflammatory cytokines. A similar response is provoked by a substantial volume of necrotic tissue, e.g. gangrenous leg, and is worse if the tissue is infected. These paracrine responses are beneficial in a local sense, combating infection by increasing blood flow and vascular permeability to allow influx of dendritic cells and macrophages, and activating neutrophils to degranulate and release cytotoxic oxygen radicals. If the stimulating factor is great, a cascade is initiated which leads to sepsis and MODS. Superoxide radicals and other circulating factors then damage cells elsewhere, causing widespread vasodilatation and increased vascular permeability leading to hypotension and circulatory collapse. The myocardium is depressed and cellular metabolic functions are disrupted.

Prevention of sepsis and MODS: Prevention and early treatment of MODS is summarised in Box 3.3.

Surgical aspects: In surgical patients, multiple organ dysfunction often results from a complication such as a bowel anastomotic leak or from severe acute pancreatitis (which may be sterile but becomes devastating if infected). Tissue necrosis following trauma, or death of an ischaemic limb may also precipitate the syndrome.

Organ dysfunction often begins insidiously. At an early stage, dysfunction can be confirmed by investigation and active resuscitation and treatment of causative factors are likely to have beneficial effects. By 7–10 days without effective treatment, pulmonary failure (ARDS) and hepatic and renal failure appear; MODS is now present and the prognosis becomes substantially worse.

Preventing sepsis and early management of major gut-related infection before it provokes the SIRS–MODS cascade is vital. Appropriate use of prophylactic antibiotics in bowel surgery or trauma helps, but intraoperative and postoperative errors in technique or clinical judgement are major factors in more than 50% of patients with multiple organ dysfunction. Good clinical judgement, effective resuscitation, good operative technique, effective excision of necrotic tissue, minimising bacterial contamination and preventing accumulation of postoperative fluid collections (serum or blood) are all necessary for prevention. The purpose is to eliminate environments in which bacteria multiply and improve the delivery of host antibacterial defences.

Surgical complications with septic potential should be treated early, usually by definitive surgery, e.g. removal of necrotic tissue, drainage of abscesses and control of peritoneal contamination by exteriorising leaking anastomoses. This helps reduce the circulating level of inflammatory mediators and limits the period of stress. It is often better to perform a laparotomy on suspicion and find it normal than to ‘wait and see’ and risk rapid deterioration and death.

Other preventive factors in at-risk patients: Adequate and early fluid resuscitation is vital in patients with hypovolaemia, including in trauma victims, acute pancreatitis or bowel obstruction, because the loss of intravascular volume leads to deficient tissue perfusion (i.e. shock) and splanchnic ischaemia. Maintaining tissue oxygenation is also vital; at-risk patients must have arterial blood gases and pH estimated and receive supplemental oxygen or assisted ventilation as required. To help prevent intestinal bacterial translocation, enterocytes and colonocytes are best supported by enteral feeding, if necessary by a feeding jejunostomy or a fine-bore nasogastric tube. Glutamine, arginine and omega-3 fatty acids are believed to be important.