Prognosis Mortality rate for cardiogenic shock was 80 \200\22390% in the 1970s and 1980s, b ut shows a continuous decrease with the use of aggressive reperfusion strategies and of the IABP. The mortality is now 55 \200\22365%, with the exception of unchanged high mortality in patients with ventricular Table 26.3.1 Vasopressor and inotropic drugs Drug Dose Heart rate Contractility Vasoconstriction Vasodilation 1 \200\2234 g/kg/min Dopexamine ++ + 0 + 1 \200\2235 g/kg/min Dopamine ++ ++/+++ ++/+++ 0 0.1 \200\2230.5 g/kg/min Norepinephrine + ++ ++++ 0 0.1 \200\2230.5 g/kg/min Epinephrine ++++ ++++ ++++ ++ at low dose only 2 \200\22320 g/kg/min Dobutamine ++ ++++ 0 ++ Bolus 50 g/kg over 10 minutes 0.375 \200\2230.75mcg/kg/min Milrinone + +++ 0 ++ Levosimendan Bolus 6 \200\22312mcg/kg 0.05 \200\2230.2 g/kg/min + ++++ 0 +++ 454 G VOGA septum rupture. Mortality is similar in patients with STEMI and NSTEMI. Predictors of morta lity are increasing age, prior MI, severe clinical manifestation on admission, oligu- ria, low EF, and MR by echocardiography, three-vessel or left main coronary artery disease and u nsuccessful revas- cularization. Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) tri al. Circulation 1997; 96: 122 \200\2237. Cotter G, Kaluski E, Milo O, et al. LINCS: l-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock: a pro- spective randomized study. Eur Heart J 2003; 24: 1287 \200\22395. French JK, Feldman HA, Assmann SF, et al. In \202 uence of thrombolytic therapy, with or w ithout intra-aortic balloon counterpulsation, on 12-month survival in the SHOCK trial. Am H eart J 2003; 146: 804 \200\22310. Further reading Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the managem ent of patients with ST-elevation myocardial inf- arction. J Am Coll Cardiol 2004; 44: 671 \200\223719. Hochman JS Cardiogenic shock complicating acute myocardial inf- arction: expanding the para digm. Circulation 2003; 107: 2998 \200\223 3002. Babaev, A, Frederick, PD, Pasta, DJ, et al Trends in management and outcomes of patients wi th acute myocardial infarction compli- cated by cardiogenic shock. JAMA 2005; 294: 448 \200 \22354. Picard MH, Davidoff R, Sleeper LA, et al Echocardiographic predic- tors of survival and r esponse to early revascularization in cardio- genic shock. Circulation 2003; 107: 279 \200 \22384. Barron HV, Every NR, Parsons LS, et al. The use of intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction Am Heart J 2001; 141: 933 \200\2239. The TRIUMPH Investigators. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: The TRIUMPH randomized controlled trial. JAMA 2007; 297: 1657 \200\22366. Berger PB, Holmes DR, Stebbins AL, et al. Impact of an aggressive invasive catheterization and revascularization strategy on mortal- ity in patients with cardiogenic shock in the Glo bal Utilization of This page intentionally left blank 456 K SIM & N WEBSTER Anaphylactic shock to the critical illness. The intubated patient provides a diag- nostic challenge as early f eatures of anaphylaxis are likely to go unnoticed. Thus a high level of clinical suspicion must be maintained. It must be remembered that anaphylactic reactions, although typically r apid in onset, may occasion- ally develop over a number of hours. Anaphylactic shock is a life-threatening multi-system disor- der, caused typically by an Ig E-mediated type 1 hypersensi- tivity reaction. The incidence of anaphylactic reactions is d if \201 cult to quan- tify (no consensus on de \201 nition); however, a recent sympo- siu m suggested that any \200\230allergic reaction that is rapid in onset and may cause death \200\231 is, by de \201 nition, anaphylactic. It is estimated that 1 in 3000 in-patients ( in the USA) suffer an anaphylactic reaction \200\2241% of all anaphylactic reactions are fa tal, so prompt recognition and treatment of the con- dition is essential. Critical care cli nicians are likely to encounter patients suffering anaphylaxis from drugs administered in t he critical care setting or in patients referred to ITU following a reaction. Cutaneous \200 Flushing \200 Angioedema \200 Urticaria Respiratory \200 Cough \200 Hoarseness \200 Stridor \200 Bronchospasm \200 If ven tilated a sudden rise in airway pressures may be noted Pathophysiology Allergy to a substance occurs via a number of steps. 1 On \201 rst exposu re to an allergen, IgE antibodies speci \201 c Cardiovascular \200 Palpitations \200 Tachycardia \200 Arrhythmias \200 Hypotension \200 Collapse to that allergen are produced by B cells. 2 These antibodies bind to mast cells and basophils and cause them to be \200\230sensitized \200\231. 3 Further exposure to the allergen causes cross-linking of bound IgE, resulting in degranulation. Mast cell degranulation leads to the release of a number of vasoactive mediators including histamine, prostaglandins, tryptase, platelet-activating factor and leukotrienes. The combi ned effect of these mediators is to produce vasodila- tation, increased vascular permeabili ty, oedema and, in cases of anaphylaxis, smooth muscle spasm in the respira- tory and GI tr acts. Chemotactic mediators are also released, attracting eosinophils to the site of in \202 ammation. Anaphylactoid-type reactions cause mast cell degranula- tion with release of mediators, as above, but do not involve IgE cross-linkage and so do not require prior expo sure to the causative agent. Clinical features and management are identical to those of ana phylactic reactions. Differential diagnosis Other conditions which should be considered when faced with the above symptoms and signs in clude: \200 \200 \200 \200 \200 Acute asthma attack/bronchospasm Tension pneumothorax Myocardial infarction Airway obstruct ion Acute hypovolaemia Table 26.4.1 Typical precipitants of anaphylaxis on ICU Clinical approach History \200 Antibiotics \200\224most commonly penicillins; cross-sensitivity of 10% with cephalosporins must be remembered In any patient presenting with unexplained collapse, it is essential to obtain an allergy h istory as soon as possible and to consider anaphylaxis in the differential diagnosis. Ascer tain history of previous allergic reactions prior to exposing patients to any potential all ergens. Of particular importance in the critical care setting is allergy to antibiotics. Al lergy to kiwi fruit is of importance as cross-sensitivity to latex is well documented. Alle rgy to eggs or soya should prompt caution in the use of propofol as it contains soya bean o il and egg phos- phatide. It must be remembered that although prior exposure to an allergen is usually necessary, cross-sensitivity may occur, e.g with penicillins and cephalosporins , and in the case of anaphylactoid reactions no prior exposure is required. Plasma expanders \200\224gelatins, starches, etc. Muscle relaxants \200\224suxamethonium and atracurium most commonly Latex Blood products \200\224rare Immediate management \200 Stop administering any potential trigger agents; in a criti- cal care setting classical tri ggers would include antibiot- ics (vancomycin is a well known trigger of anaphylactoid reac tions), muscle relaxants (particularly suxametho- nium), gelatins, latex and radiocontrast materials. ABC approach to assessment and resuscitation. 100% oxygen and obtain a de \201 nitive airway, i.e intuba- tion, if necessary. Lie the patient \202 at and elevate the le gs. Administer epinephrine in increments of 50mcg IV until blood pressure and/or bronchospa sm improves, if IV \200 \200 Symptoms and signs Anaphylaxis is dif \201 cult to recognize in the unstable criti- cally ill patient. The presenting features may be attributed 457 CHAPTER 26.4 Anaphylactic shock Referral should be made to either a dermatologist or an immunologist with a detailed record of events including all drugs being administered, so that skin prick testing can be arrang ed to determine the cause of the reaction. The reaction should be reported to the Committee on Safety of Medicines (CSM). access has been lost, a bolus of 500mcg may be adminis- tered IM repeated after 10min as ne cessary. IV \202 uids should be administered to assist in blood pres- sure control. If th e patient is known to be taking TCAs or MAOIs, it is advised that the dose of epinephrine u sed should be halved. If hypotension is refractory to epinephrine, vasopressin may be consi dered as an alternative agent. Patient advice The patient should be given advice regarding what sub- stances are potential triggers to avoid furthers attacks. The importance of informing any medical staff who subs e- quently care for the patient about the nature of, and trig- gers for, their reaction mus t be stressed. In some circumstances, depending on the trigger, it may be appropriate to pr escribe a preloaded syringe of epine- phrine for the patient to self-administer in case of further attacks; this decision would ideally be made by the immu- nologist following up the patient. Subsequent management \200 An antihistamine should be given, usually chlorphe- niramine 10 \200\22320mg IV. Hydrocorti sone in a dose of 100 \200\223300mg IV should be given. A catecholamine infusion (epinephri ne or norepine- phrine) may be required, as cardiovascular instability may persist for hour s. Nebulized salbutamol may be required to aid bron- chodilatation; if persistent, IV salbu tamol may be consid- ered. Prior to extubation the cuff of the ETT should be de \202 ated and an air leak appreciated to ensure adequate resolution of any airway oedema. Further reading Ewan PW. ABC of allergies: anaphylaxis. BMJ 2007; 316: 1442 \200\2235. Neug ut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its ep idemiology. Arch Intern Med 2001; 161: 15 \200\22321. Project team of the Resuscitation Council (UK). The emergency medical treatment of anaphyla ctic reactions for \201 rst medical responders and for community nurses. 2005. www.resus. org.uk Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second sympo- sium on the de \201 nition and management of anaphylaxis: summary report \200\224Second National Institute of A llergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Cli n Immunol 2006; 117: 391 \200\2237. Investigations/follow-up No investigations are helpful during the acute event and so should be deferred until the patient is stabilized. Serum for a mast cell tryptase level should b e taken 1h post-reaction to obtain peak levels and 5h post-reaction to ensure the level is falling. Levels will be high in both true anaphylactic and anaphylactoid reactions. Serum tryptase has a half-life of 2.5h and a basal level of 0.8 \200\2231.5ng/ml; levels >20ng/ml may be seen in true anaphylaxis. It may also be useful to send blood for complement and Ig E levels at this time. Stephenson TJ. Immunology and immunopathology. In: Underwood JCE, ed. General and systemati c pathology, Edinburgh: Churchill Livingstone, 1996: 192 \200\2235. 458 J DOWN Septic shock: pathogenesis Septic shock is de \201 ned as sepsis-induced refractory hypo- tension despite adequate \202 uid resuscitation, along with the presence of hypoperfusion abnormalities or organ dys func- tion. The hypotension is mainly due to a drop in SVR sec- ondary to vasodilation. The re is, however, often concurrent myocardial depression. It is the most severe end of a spec - trum of syndromes caused by entry into the bloodstream of microbiological pathogens. Toxi ns released by these pathogens invoke an in \202 amma- tory response by the host. This res ponse must be a \201 nely controlled balance of in \202 ammation, coagulation and \201 bri- nolysis. Loss of this balance may lead to septic shock. One \201 nal pathway common to both Gram-positive and Gram-negative sepsis is via cell su rface Toll-like receptors. These receptors activate nuclear transcription factors (such as NF- B) which stimulate the nucleus to release cytokines and other in \202 ammatory mediat ors. Whilst the cytokine pro \201 le of the two major forms of sepsis may differ slightly, the overall response, disease progression and mor- tality are similar. Host response In \202 ammation Stimulation of macrophages initiates an inflammatory respon se to infection with the aim of destroying damaged tissue and promoting wound healing. This is followed by release of anti-in \202 ammatory mediators to dampen the in \202 ammatory response and maintain homeostasis. In sep- sis, this balance is lost. Initially excessive in \202 ammation leads to a procoagulant state, widespread endothelial dysfunc- tion, MOD and shock. This is followed by excessive anti- in \202 ammatory activity leading to immuno suppression and increased susceptibility to secondary infection. Pathogens Bacteria account for 90% of cases of sepsis in which patho- gens are identi \201 ed, fungi (mainly Candida) make up a fur- ther 5% (probably increasing, up to 20% in the U SA) and mixed bacterial/fungal/viral infections make up the \201 nal 5%. In 30 \200\22340 % of cases no pathogen is identi \201 ed. Gram-negative infection has been traditionally a ssociated with development of septic shock. However, the propor- tion of cases caused by Gr am-positive organisms has recently escalated. This is likely to be related to the increased instrumentation of patients. Proin \202 ammatory Figure 26.5.1 shows a simpli \201 ed overview of the in \202 amma- t ory response. In reality, many complex physiological resp- sonses occur simultaneously. Mac rophages release many in \202 ammatory cytokines and mediators, e.g. IL-6, IL-1, TNF and N O. These in turn stimulate selectins which attract neutrophils to the site of in \202 amma tion and aid with their degranulation and adhesion to the endothelium. The cytokines also a ctivate platelets and T lymphocytes which release further cytokines, eg. IL-2 and interfero n- . The resulting endothelial damage results in release of tissue fac- tor, which is a ke y link between the immune and coagulant systems and results in a procoagulant state. Initiation of the disease process Gram-negative sepsis Endotoxin (lipopolysaccharide (LPS)) is the most investi- gated component in triggering Gram-negative sepsis. It is found in th e cell wall of the bacteria and, following infec- tion, binds to serum proteins. It then in teracts with CD14 receptors found on the surfaces of various cells, including leucocytes an d endothelia cells. Gram-positive sepsis A variety of toxins are harbored by different Gram-posi- tive bacteria . These comprise cell wall components (such as lipoteichoic acid and peptidoglycan) and ext racellular products (such as pore-forming enzymes and superanti- gens). Lipoteichoic acid i nteracts with CD14 receptors in a similar way to LPS, but the other products have a diverse range of toxic mechanisms. Anti-in \202 ammatory Macrophages subsequently release anti-inflammatory mediators such as IL-10 and IL-13, which counteract the actions of IL-6, IL-1 and TNF. This response is ofte n insuf \201 - cient in the early stages of sepsis and excessive later in the disease. Infection and macrophage activation Release of anti-inflammatory cytokines eg IL-10, IL-13 Release of pro-inflammatory Mediators eg IL -6, IL-1, TNF Neutrophil activation and Degrannulation causing release of free radicals and proeases Platelet activation and aggregation T cell activation leading to release of IL-2 and interferon Endothelial dysfunction Release of tissue factor causing micro-thrombi formation Fig. 26.5.1 Simpli \201 ed view of the in \202 ammatory response. 459 CHAPTER 26.5 Septic shock: pathogenesis rection of relative adrenal insuf \201 ciency and hyperglycaemia may improve outcome, this remains controversial Vascular endothelium The endothelium is a dynamic participant in cellular and organ functio n. During in \202 ammation, activation or damage of endothelial cells results in increased capillary leak, allow- ing ingress of \202 uid migration of leucocytes to the point of i njury. Endothelial damage also leads to release of tissue factor which stimulates coagulati on and inhibits \201 brinolysis. This response is usually then downregulated by anti-in \202 am- matory and anticoagulant mediators expressed by the endothelium. However, in sepsi s, excessive damage to the endothelium results in loss of this regulatory function, resulti ng in inappropriate cytokine release, thrombus for- mation, regional areas of vasodilation and vasoconstriction, shock and generalized tissue damage. Mechanisms of shock Hypotension in septic shock is cause by a combination of changes to the peripheral circulation and myocardial func- tion. The peripheral circulation alters in thr ee ways. Prostaglandins and NO cause peripheral vasodilation, cytokines increase capillary leak which results in intravas- cular hypovolaemia, and vascular smooth muscle becomes hypo reactive to sympathetic stimulation. The vascular hyporeactivity is a consequence of a comb ination of down regulation of A adrenergic receptors, excessive activation of potassium cha nnels, disruption of intracellular calcium homeostasis and relative vasopressin de \201 ci ency. Although cardiac output is often increased in septic shock, there is good evidence of myocardial depression. This is caused by a combination of cytokines, NO and other myocardi al depressant factors. Coagulation Sepsis induces a procoagulant state by several mechanisms. The interaction of n eutrophils with platelets causes micro- thrombi formation. Damaged endothelium releases tis sue factor which stimulates the coagulation cascade and depo- sition of \201 brin. Endoge nous anticoagulant factors such as protein C, antithrombin and heparin sulfate are depleted , and activation of plasminogen activator inhibitor-1 down- regulates the production of pla smin and thus reduces \201 bri- nolysis. This results in the laying down of thrombi in th e microvasculature. It also, paradoxically, induces an increased tendency to bleeding due t o consumption of procoagulant factors and platelets. The most severe form of coagulaopa- th y is the syndrome of DIC. The clinical signi \201 cance of microthrombi is uncertain; howe ver, thrombin is a highly potent proin \202 ammatory mediator. Necrotizing fasciitis Necrotizing fasciitis is a bacterial infection of soft tissue that spreads insidiously alon g fascial planes. It may be divided according to the causative organism into type 1 or poly microbial, type 2 caused by Group A B haemolytic Streptococcus and type 3 gas gangrene caus ed by clostridia. Types 1 and 3 commonly follow trauma or surgery whereas type 2 can occur de novo. Pathophysiology The spread through the fascial planes is facilitated by bac- terial enzymes and toxins. Dee p-seated infection causes vascular occlusion and tissue necrosis. Destruction of superficia l nerves causes a characteristic anesthesia. Group A B haemolytic Streptococcus release dir ectly toxic streptococcal pyrogenic exotoxins which, combined with streptococcal superantig ens, cause massive release of cytokines and septic shock. The pathogenicity is further enha nced by the expression of surface proteins M1 and M3 which facilitate adherence to tissues and inhibit phagocyto- sis by neutrophils. This combination gives the condition a mortality of 20 \200\22370%. Nitic oxide NO is produced by various cells primarily by NOS. Three types of NOS have been identi \201 ed, endothelial constitutive NOS (ecNOS) neuronal NOS (nNOS) and inducible NOS (iNOS). ecNOS and nNOS are produced by healthy cells and play a part in normal regulation of blood \202 ow and cell signaling. However, in the presence of in \202 ammation, they are downregulated while iNOS production is upregulated. iNOS produces excessive NO for a pr olonged period. The overproduction of NO causes mitochondrial inhibition and extensive syst emic vasodilation which can be refractory to vasopressors. This, may lead to sustained hypo tension, the de \201 ning feature of septic shock. Further reading Bone RC, Balk RA, Cerra FB, et al. De \201 nitions of sepsis and organ fai lure and guidelines for the use of innovative therapies. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1 992; 101: 1644 \200\22355. Mitochondria In sepsis, organs can fail despite adequate tissue oxygen tensions. This impli es a problem with oxygen utilization. 90% of oxygen utilization within most cells is mitoch ondrial respiration and generation of ATP. In \202 ammatory mediators including NO and oth er reactive species can impair mito- chondrial function. The subsequent decrease in energy supply may lead to a fall in cellular metabolism manifest as organ dysfunction. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors and outcomes of severe se psis and septic shock in adults. JAMA 1995; 274: 968 \200\22374. Kidokoro A, Iba T, Fukunaga M, et al. Alterations in coagulation and \201 brinolysis during sepsis. Shock 1996; 5: 223 \200\2238. McGill SN, Ahmed NA, Christou NV. Endothelial cells: role in infec- tion and in \202 ammation. World J Surg 1998; 22: 171 \200\2238. Endocrine Septic shock is often associated with alterations in hor- mone expression. Thyroi d and adrenal function are often depressed, and insulin resistance is common. Estrogen leve ls are often high, and testosterone and leptin levels low. The presence of these endocrine abnormalities in sep- tic shock is associated with a poor outcome, but causation remains un clear. While some studies have suggested cor- Opal SM, Cohen J. Clinical Gram-positive sepsis: does it fundamen- tally differ from Gram-n egative bacterial sepsis? Crit Care Med 1999; 27: 1608 \200\22316. Sriskandan S, Cohen J. Gram-positive sepsis. Mechanisms and differ- ences from Gram-negativ e sepsis. Infect Dis Clin North Am 1999; 13: 397 \200\223412. Stewart TE, Zhang H. Nitric oxide in sepsis. Respir Care 1999; 44: 308 \200\22313. This page intentionally left blank 461 Chapter 27 Infection and in \202 ammation Chapter contents Pathophysiology of sepsis and multi-organ failure 462 Infection control \200\224general pri nciples 464 HIV 466 Severe falciparum malaria 468 Vasculitides in the ICU 470 Source contro l 472 Selective decontamination of the digestive tract (SDD) 474 Markers of infection 476 A drenal insuf \201 ciency and sepsis 478 462 M GARRIOCH Pathophysiology of sepsis and multi-organ failure proin \202 ammatory mediators such as the cytokines and interleukins (IL-1 and IL-6) and a lso enzymes such as iNOS and cyclo-oxygenase-2 (COX-2). NF- B regulates the immune respons e. Pathogens also stimulate the arachidonic acid cascade, within endothelial cells generati ng further proin \202 ammatory prostaglandins, thromboxanes and leukotrienes. Activated ne utrophils also produce and release large quantities of proteases, hydrogen peroxide and rea ctive oxygen species. Thus a \200\230storm \200\231 of pathological substances causes the characteristic effects of sepsis, \200 Infectious agents entering the body lead to local in \202 amma- tion, pus and abscess form ation, and affect the whole body through systemic in \202 ammation. Systemic in \202 amma tion is recognized by the presence of fever, abnormal WCC, and increased heart and respirat ory rate, and is known as systemic in \202 ammatory response syndrome (SIRS). If SIRS is d ue to infection (as distinct from other causes such as pan- creatitis, burns or major traum a) it is de \201 ned as sepsis. The body, or host, reacts to infection by two mechanisms, the innate and adaptive immune systems. The innate immune system comprises mast cells, phag ocytes (macrophages, neutrophils and dendritic cells), basophils, eosinophils and natural k iller cells, and defends the body by non-speci \201 cally reacting to foreign materials th at enter the body. It also acti- vates the adaptive immune system via T and B lymphocytes. The adaptive immune response is more speci \201 c, recognizes speci \201 c pathogens and generates immunity to them by anti- bodies. These two immune responses effectively combat m inor infections. When this process becomes exaggerated sepsis results. In sepsis, three pro cesses are involved, 1 Recognition of microbial material as foreign to the body. 2 Immediat e release of histamine, bradykinin, serotonin and leukotrienes, causing vasodilatation of t he local microcirculation and attracting neutrophils to form pus. 3 Leucocytes and other ce lls lyse, destroy and mop up for- eign material and microbes, neutralizing the infectious c hallenge. Increased vascular permeability allowing the passage of \202 uid, plasma proteins and act ivated neutrophils into the extravascular space. Microcoagulopathy. Alterations in microvas cular tone. Possible alteration in the epithelial tight junctions in the lung, liver and gu t, thereby promoting translocation of bacteria into the circulation adding still further to the septic process and organ failure \200 \200 The gross effect of these changes is hypovolaemia with interstitial oedema, blood \202 ow redistribution and tissue hypoxia. Although antibiotics and/or surgical intervention \200 \230cure \200\231 sepsis, adequate \202 uid loading to compensate for tis- sue \200\230l eak \200\231, inotropic support to maintain cardiac output and good oxygenation are essenti al supportive treatments for advanced sepsis. TLRs and NF- B also show that there are sign ificant genetic in \202 uences on a patient \200\231s response to infection and are import ant future areas of study. If local processes are overwhelmed, the invading organism is particularly virulent or treat ment is inadequate, progres- sion to systemic in \202 ammation and sepsis occurs. Sepsis c an affect any major organ and potentially results in organ failure. Septic shock occurs whe n the effects of abnormal microcirculatory \202 ow become apparent and perfusion of organ s is affected. This is characterized by excessive vasodilatation, vascular hyporeactivity ( decreased responsiveness to catecholamines) and variable degrees of myocardial depression, leading to hypotension that is unre- sponsive to \202 uid resuscitation. These changes re sult from excess NO, excessive activation of potassium channels and inappropriately low cir culating levels of vasopressin. Cytokine production Cytokines are implicated in SIRS, in \202 ammatory and immu- nological diseases and may be pro- or anti-in \202 ammatory. They are small water-soluble proteins and glycoproteins which are produced very quickly by leucocytes, mast cells, epithelial cel ls and endothelial cells. Some enhance the microbiocidal effects of phagocytosing cells, re cruit leuco- cytes to the site of infection, enhance haematopoesis, produce fever and induc e most of the physiological changes associated with sepsis and septic shock. Predominantly proin \202 ammatory cytokines include IL-1, IL-12, IL-18, TNF- , interferon- and granul ocyte \200\223 macrophage colony-stimulating factor (GM-CSF). Proin \202 ammatory cytokine s contribute to the anti-infectious process but their excess production leads to tissue dam age. Anti-inflammatory cytokines are IL-4, IL-10, IL-13, interferon- and transforming gro wth factor- (TGF- ). Anti-in \202 ammatory cytokines are useful in damping in \202 am- mation, but their excessive production may cause immuno- depression. Attempts at therapeut ic cytokine administration have failed to modify sepsis, probably because the septic path- way is too complex to be in \202 uenced by the absence or presence of any one cytokine. Recognition of pathogenic materials in the body and regulation of genetic transcription Pat hogens have patterns of exogenous molecules on their surface, pathogen-associated molecular patterns (PAMPs). These include endotoxin (LPS), lipoproteins, outer membrane proteins, \202 agellin, \201 mbriae, peptidogly- can, peptidoglycan-associated lipoprotein and lipo teichoic acid. Other molecules become PAMPs when bacterial lysis occurs and heat shock prot eins and fragments of DNA are released. PAMPs are recognized by Toll-like receptors (TLRs) and cytoplasmic \200\230pattern recognition receptors \200\231 (PRRs). TLRs are the key mo lecules embedded in cell membranes, which alert the immune system to the pres- ence of micr obes and trigger a host response. Thirteen TLRs have been identi \201 ed and are the bridg e between the innate and adaptive immune systems. Interaction between TLR and IL-1 receptor s, so-called Roll-IL-1 receptors (TIRs), activate the transcription nuclear factor- B (NF- B), a pro- tein complex found in all cell types. NF- B is involved in the cellular respo nses to any damage from shear stress, cytokines, free radicals, ultraviolet irradiation, an d bacterial or viral antigens. It upregulates expression of genes encoding Immune cells (leucocytes) Infection stimulates bone marrow production of leucocytes that ar e released into the blood as newly differentiated or immature cells. Chemotactic agents and adhesion molecules facilitate migration of activated leucocytes from the blood- stream to in \202 ammatory tissues. These phagocytose and 463 CHAPTER 27.1 Pathophysiology of sepsis and multi-organ failure This differs from necrosis, cell death resulting from injury. Fas bacteria-mediated epithel ial cell apoptosis contributes to immune defenses via activation of the Fas/Fas ligand sys- tem and thus can help the septic process by \200\230sacri \201 cing \200\231 infected ce lls by use of cytotoxic T cells. The role of apop- tosis in septic shock is unclear, but it may exacerbate or promote the cellular damage associated with sepsis. destroy infectious agents, while monocytes, tissue macro- phages and other myeloid-derived cells release cytokines. Leucocytes also release proteases, e.g. elastase, that play a pivo tal part in combating infections. Increased concentra- tions of elastase found in plasma an d bronchoalveolar lav- age \202 uid might contribute to shock and organ dysfunction. The terms anergy, immunodepression or immunoparalysis are also commonly used to describe the im mune status of septic patients. Ex vivo studies suggest that the responsive- ness of leucoc ytes to infection can be blunted by exposure to LPS and IL-10. Negative regulators of TLR-d ependent signaling pathways probably exist but are not yet identi- \201 ed. Overwhelming sepsis does depress immune function. Conclusion Sepsis is a complex and multi-factorial disease. Normal immune and neuroendocrin e systems that defend the body against infection can be overstimulated, and systemic in \202 ammation occurs to the point that it affects the whole body and becomes detrimental. A cascade of disrupted microcirculatory blood \202 ow, excess activation of coagula- tion and adversely affected organ function results. Understanding the complexity and controlling sepsis is one of the great medical challenges of our time. Endothelium Constitutive nitric oxide synthase (cNOS) is an enzyme secreted from within the endothelium to produce the potent vasodilator NO. NO acts to dilate pre-capillary sphincte rs at the entry to the microvascular capillaries regulating blood \202 ow to tissues. In sepsis, this process is disrupted by NF- B, stimulating production of an additional enzyme called iNOS which produces excess NO and thus excessive vasodilatation. The normal microva scular \202 ow is disrupted and there is indiscriminate alteration of perfusion and incre ased vascular permeability. This contributes to the poor perfusion associated with septic s hock, and tissue blood \202 ow can be abnormal despite the appearance of a high cardiac o utput. Unfortunately, attempts to modulate cNOS have proved unsuccessful in improving clini cal outcome from sep- tic shock. Drugs which modify iNOS are not available. Further reading Bernard GR, Vincent JL, Laterre PF, et al. Ef \201 cacy and safety of reco mbinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699 \200\22370 9. Bone RC, Fisher CJ, Clemmer TP, et al. Sepsis syndrome: a valid clinical entity. Methylpred nisoline Severe Sepsis Study Group. Crit Care Med 1989; 17: 389-93. Boveris A, Alvarez S, Bustamante J, et al. Measurement of superox- ide radical and hydrogen peroxide production in isolated cells and subcellular organelles. Methods Enzymol 2002; 34 9: 280 \200\2237. Buckley JF, Singer M, Clapp LH. Role of KATP channels in sepsis. Cardiovasc Res 2006; 72: 220 \200\22330. Kaisho T, Akira S. Toll-like receptors as adjuvant receptors. Biochim Biophys Acta 2002; 1589: 1 \200\22313. Coagulation and sepsis Coagulation and sepsis are interlinked. TNF- , IL-1 and IL-6 are al l capable of activating coagulation and inhibiting \201 brinolysis. The procoagulant thro mbin is capable of stimu- lating multiple in \202 ammatory pathways. These interactions pr omote diffuse endovascular injury, MOD and death. The importance of APC in coagulation and sepsis is now known. Reduced levels of protein C are found in the major- ity of patients wi th sepsis. APC is an endogenous protein and is converted from its inactive precursor, prote in C, by thrombin coupled to thrombomodulin. This conversion may be impaired during sepsis as a result of the downregu- lation of thrombomodulin by inflammatory cytokines, excess thr ombin and a worse outcome from septic shock. APC promotes fibrinolysis, inhibits thrombosis and decreases in \202 ammation. When supplemental APC is infused into patients with advan ced sepsis, mortality is reduced. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345: 588 \200\22395. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, d ouble-blind study of the nitric oxide syn- thase inhibitor 546C88: effect on survival in pa tients with septic shock. Crit Care Med 2004; 32: 21 \200\22330. Singer M, De Santis, V, Vitale D, et al. Multiorgan failure is an adap- tive, endocrine-med iated, metabolic response to overwhelming systemic in \202 ammation. Lancet 2004; 364: 545 \200\2238. Thiemermann C. Nitric oxide and septic shock. Gen Pharmacol 1997; 29: 159 \200\22366. Tsiotou AG, Sakorafas GH, Anagnostopoulos G, et al. Septic shock; current pathogenetic conc epts from a clinical perspective. Med Sci Monit 2005; 11: RA76 \200\2238. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and \201 brinolysis in critic ally ill patients with sepsis and septic shock. Semin Thromb Hemostasis 1998; 24: 33 \200 \22344. Yan SB, Helterbrand JD, Hartman DL, et al. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001: 120: 915 \200\22322. Neuroendocrine function Damage caused to tissues during sepsis is not purely due to ischaem ic or haemorrhagic processes. Some tissues iso- lated from recovered patients are remarkabl y normal. More subtle changes induced by TNF, IL-1 , NO and reac- tive oxygen species inhi bit the mitochondrial respiratory chain, reducing energy production through aerobic respira - tion. This is aggravated by malfunction of the sympathetic nervous system. This again emp hasizes how complex the septic process is, and the interplay between the sympa- thetic nerv ous system, sympathomimetic drugs and organ metabolism in sepsis is incompletely understood . Apoptosis When an epithelial cell becomes infected its membranes may display a transmembran e ligand known as a Fas ligand. Fas ligands bind cytokines and kill the affected cell; thus this is a kind of \200\230suicide \200\231 mechanism for cells that become infected. This is a form of programmed cell death or apoptosis. 464 R DAVIS Infection control \200\224general principles The majority of patients admitted to critical care units will receive treatment for infecti on at some time. Around a third will develop a nosocomial infection; rates of health- care- associated infection are 3 \200\2235 times higher than for gen- eral ward patients. A varie ty of factors in ICU lead to increased risks of infection with and transmission of multi- r esistant organisms. These include 1 critically ill (often imunosuppressed) patients 2 frequ ent use of in-dwelling devices 3 prescription of broad spectrum antimicrobials, often in angle and avoiding gastric distension. NIV should be used when appropriate to avoid endotra cheal intubation. The use of selective digestive decontamination remains contro- versial (s ee Chapter 27.7). Diagnosis of VAP is dif \201 cult, but invasive diagnostic meth- ods usi ng quantitative culture of a bronchoscopic pro- tected specimen brush or bronchoalveolar la vage samples can improve speci \201 city of the diagnosis. These techniques have been asso ciated with decreased antibiotic use with- out any increase in mortality. combination Urinary catheters Catheter-associated UTI is the most common nosocomial infection in hospit als, with cumulative rates increasing with length of time the catheter is in situ. The use of silver alloy catheters in hospitalized patients requiring short- term catheterization ap pears to reduce rates of catheter- associated UTI. Most importantly, local guidelines shoul d be followed for care of urinary catheters, with early removal of the catheter if possible . 4 intensive nursing/medical contact that can lead to cross- transmission of organisms. Hospital ICU infection control guidelines, although based on national and international gui delines, should re \202 ect local conditions. The \200\230Winning Ways \200\231 report (U K) summarizes recommendations for reducing nosocomial infections. Prevention of infection related to devices Intravascular catheters Approximately 39 per 100 0 patients in English ICUs develop device-related bacteraemia, with the vast majority of th ese being due to CVCs. Catheter-related blood- stream infections (CR-BSIs) are most commonl y caused by skin organisms that colonize the exit site and catheter hub. These may contamin ate the catheter during inser- tion or be transferred from the hands of staff during care i nterventions. Coagulase-negative staphylococci such as Staphylococcus epidermidis are most commonly implicated, followed by S. aureus, Candida species and enterococci. A range of tec hniques is associated with reduced rates of CR-BSI. \200 Prudent antimicrobial use Empiric therapy, started after cultures are taken, is usually gui ded by local antibiotic policy. Proper collection of speci- mens and careful interpretation of culture results helps to differentiate between organisms that are contaminating specime ns or colonizing the patient and organisms that are causing infection. Therapy should be ad justed to the nar- rowest spectrum effective antimicrobial based on culture results, and an tibiotics should be stopped as soon as there is cure or if no evidence of infection is foun d. Involvement of infectious disease or microbiology clini- cians improves patient outcomes and decreases treatment costs in serious infections.