uinine-based alternatives include: IV quinidine gluconate 10mg/kg loading dose (max- imum 6 00mg) over 1 \200\2232h, then continuous infusion of 0.02mg/kg/min or IV quinine dihydrochl oride 20mg salt/kg loading dose over 4h followed by 10mg/kg over 2 \200\2234h every 8h (max 1800mg/day). Patients who received me \202 oquine or other quinine derivatives within the previous 12h should not receive a loading dose. Changes in the volume of distri- bution me an doses need to be reduced by 33 \200\22350% after 2 days. Some centers monitor quininine levels daily. Cardiac monitoring is required during IV infusion, and hypoglycae- mia is a s igni \201 cant risk especially as malaria is associated with hyperinsulinaemia. Other treatments Exchange transfusion is considered in P. falciparum infec- tion when paras itaemia is >10% and in patients with coma, 469 CHAPTER 27.4 Severe falciparum malaria renal failure or ARDS, regardless of the level of parasitae- mia although without a strong evidence base. Studies of antipyretics, anticonvulsants (phenobarbital), anticytokine/anti- in \202 ammatory agents (e.g. anti-TNF anti- bodies, dexamethasone, pentoxifylline), iron chelators and hyperimmune sera have all been disappointing. Steroids have been used in cere bral malaria but have been associ- ated with a worse outcome than quinine alone. Heparin in creases bleeding complications and should not be given. European ICUs which may be attributed to early admission to HDU/ICU; it may also be that th is patient group selects out those prone to early cerebral malaria. Further reading Bruneel F, Hocqueloux L, Alberti C, et al. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 2003; 167: 684 \200\2239. Dondorp A, Nosten F, Stepniewska K et al. Artesunate versus qui- nine for treatment of seve re falciparum malaria: a randomized trial. Lancet 2005; 366: 717 \200\22325. Prognosis Age <3yrs, seizures, papilloedema, deep coma, decerebrate or decorticate posturin g, organ dysfunction, acidosis, respi- ratory distress and circulatory collapse are all ass ociated with a poor outcome. The mortality of untreated falci- parum malaria is close to 10 0%. The fatality rate for treated severe malaria is 10 \200\22340%. A lower mortality rate has been reported for patients with severe malaria treated in Lalloo DG, Shingadia D, Pasvol G, et al. UK malaria treatment guide- lines. HPA Advisory Co mmittee on Malaria Prevention in UK Travelers. J Infect 2007; 54: 111 \200\22321. Pasvol G. Management of severe malaria: interventions and contro- versies. Infect Dis Clin North Am 2005; 19: 211 \200\22340. WHO. Severe falciparum malaria, a practical handbook, 2nd edn. 2000. http://www.who.int/mal aria/docs/hbsm.pdf 470 R KISHEN Vasculitides in the ICU Introduction Vasculitides are a heterogeneous group of relatively uncommon diseases charact erized by destruction of the blood vessel wall and cellular inflammation. Systemic necrotiz ing vasculitides are potentially life-threatening con- ditions involving multiple organ sys tems. Their ICU out- come is poor, with in-hospital mortality of >50%. disorders and malignancies. In patients with known vasculi- tis and who deteriorate clinica lly, identifying the cause of deterioration can be equally dif \201 cult. A high index of suspi- cion and awareness, combined with a thorough review of history and detailed clinical examination are a key to early diagnosis. History may highlight conditions such as hepati- tis (associated with PAN), non-speci \201 c illness often diag- nosed as infection, low g rade fever, cough, breathlessness, anemia, headaches, a previous history of vasculitis, etc . Clinical examination may reveal evidence of the vasculitic process: nail-fold infarcts, s plinter hemorrhages, retinal hemorrhages, Roth spots (also seen in endocarditis), scleritis , episcleritis, palpable purpura, ulcerative lesions of the nose causing bloody or purulent nasal discharge, chronic otitis media, deafness and mononeuritis multiplex (sudden wrist o r foot drop, paraesthesia, numbness, etc. occurring in two or more peripheral nerve distrib utions). There may be an unusual constellation of signs and symp- toms involving multiple o rgan systems, either simultane- ously or over time. Detailed clinical findings in each cond ition are given elsewhere. Classi \201 cation Depending on the size of the vessels involved, the follow- ing disease entities of primary idiopathic vasculitis are recognized: 1 Large vessel vasculitis, e.g. g iant cell arteritis, Takayasu \200\231s arteritis 2 Medium vessel vasculitis, e.g. classical polyarteritis nodosa (PAN), Kawasaki \200\231s disease; 3 Small vessel vasculitis, e.g. Wagner \200\231s granulomatosis (WG), microscopic polyangit is (MPA), Churg \200\223Strauss syndrome (CSS), pauci-immune rapidly progressive glomerulon ephritis (RPGN), isolated pauci-immune pul- monary capillaritis, Henoch \200\223Sch nlein purpura, etc. Small vessel vasculitides sometimes have medium vessel involvement as well, a re most commonly associated with antineutrophil cytoplasmic antibodies (ANCAs; see below), are associated with high risk of glomerulone- phritis and respond best to immunosuppression with cyclophosphamide. Laboratory investigations Routine blood tests show non-speci \201 c changes such as a norm ocytic or microcytic anemia, a neutrophil leucocyto- sis and occasionally eosinophilia (in CCS). ESR (rarely measured in ICU patients) and CRP levels are both raised. Low serum album in and raised alkaline phosphatase, urea and creatinine are usual. Urine examination may sh ow blood and protein on dipstick test. Goodpasture \200\231s syndrome (primary immune complex- mediated vasculitis) and secondary vasculitis due to SLE, rheumatoid arthritis, ploymyositis, scleroderma, etc. are other vasc ulitic conditions. Serological, histopathological and radiological tests ANCAs are important adjuncts in diagn osis of ANCA- associated vasculitides (WG, CSS, MPA, etc.) where ANCA positivity is common but not universal. Two types of assays for ANCA are in common use (indirect immuno \202 uo res- cence and ELISA). Cytoplasmic ANCAs (C-ANCAs) are primarily associated with antibodies directed against pro- teinase 3 (PR3) found in azurophilic granules of neutrophils and lys osomes of monocytes, whereas perinuclear ANCAs (P-ANCAs) are commonly associated with those directed against myeloperoxidase (MPO), also found in azurophilic granules. ANCA binding t o these molecules on activated neutrophils is thought to be an important mechanism of injur y in these conditions. If immuno \202 uorescence alone is used, then C-ANCA is more speci \201 c of vasculitis than P-ANCA. All serum that is ANCA positive should be tested in PR3 and MPO ELISAs as this increases their spe- ci \201 city. A negative ANCA does not exclude the possibility of vasculitis, as there are some small vessel vasculitides that are ANCA n egative. Principles in relation to clinical utility of ANCA testing are: \200 Incidence, outcome and etiology Annual incidence of primary systemic vasculitides (WG, MPA, CSS and polyarteritis) in the UK is 20 cases per million. They usually occur in those age d in their 50s and 60s (peak incidence in ages 65 \200\22374) with male preponder- ance. Th e incidence in the UK ICUs is 0.07%, with ICU mortality of 35% and hospital mortality of 55.2%; the majority of these cases are transferred to specialist centers for management. Pr imary vasculitides (WG, MPA, CSS, etc.) arise de novo, but secondary vasculitides arise in association with an established disease such as rheumatoid arthritis, infections (hepatitis , HIV, syphilis), drugs (sulfonamides, penicillins, thiazides) and malignancy. Presentation and diagnosis in ICU patients A patient with known vasculitis may be admitted to the ICU as a consequence of their disease, e.g. respiratory fail- ure due to diffuse alv eolar hemorrhage (DAH) or acute renal failure. However, initial diagnosis of vasculitis may be made for the \201 rst time after ICU admission. In the critically ill, diagnosis is c hallenging because of variable and multi- faceted presentation, low incidence of vasculitis in the gen- eral and ICU population, and overlap of signs and symptoms with a variety of c ommon illnesses such as sepsis. positive ANCA serology is extremely useful in suggest- ing the diagnosis positive immuno \202 uorescence assays without con \201 rma- tory ELISA for PR3 or MPO are of limited valu e histopathology is the gold standard for diagnosis in most patients negative assays do not exclude vasculitis persistent ANCAs in the absence of clinical features of active disease does not mean continued treatment in ANCA-positive patients, persistent ANCA negativity dur ing remissions is reassuring but no guarantee that the disease is inactive \200 Signs and symptoms Patients may present to ICU with respiratory failure and non-speci \201 c CXR changes rather than classical renal fail- ure. Most of the signs and symptoms are no n-speci \201 c and overlap with those of infections, sepsis, connective tissue 471 CHAPTER 27.5 Vasculitides in the ICU cyclophosphamide, alternative therapies with mycofenylate mofetil, levamisol and TNF- inh ibitors have been used recently. Many newer therapies and immunosuppressants are being tria led. There are several case reports of bene \201 t of activated human factor VII in cases of DAH. ANCA positivity, following a clinical quiescence (and ANCA negativity) means a risk of \202 are-up. A plain CXR may show non-speci \201 c changes, nodular or cavitating lesions. Diffuse grou nd glass opaci \201 cation should raise suspicion of DAH and vasculitis. High resolution C T may help, but features remain non-speci \201 c. Where possible, biopsy of the lesions in the affected organs is desirable. Biopsies may be obtained from skin, nasopha- ryngeal les ions (if present) in WG and MPA. If no easily accessible lesions are seen, then the clinica l picture present decides the next most appropriate site for biopsy. In most cases in ICU, a renal or lung biopsy may be most appropri- ate. Although features speci \201 c for vascu litis are rarely seen, percutaneous renal biopsy may show focal, segmental necrotizing glom erulonephritis without immune deposits (pauci-immune) and this generally reflects a systemi c vasculitis. When lungs are involved, open lung or thoraco- scopic biopsy provides a highe r diagnostic yield than trans- bronchial biopsy. No single test is capable of distinguishin g between or even diagnosing various forms of vasculitides; a combination of history and cl inical examination as well as serological, histopathological and radiological tests are req uired to make a \201 nal diagnosis. Speci \201 c ICU management The management of these patients in the ICU is supportive in a ddition to speci \201 c immunosuppressive therapy. A few points are worthy of mention: \200 WG involves the upper respiratory tract and patients may have subglottic stenosis making in tubation potentially dif \201 cult. An ETT of smaller diameter may be needed, and tracheos tomy may be required in many. DAH and massive pulmonary hemorrhage increase early mortality . Lung protective ventilation may reduce injury to lungs and allow DAH to resolve. Permissi ve hypercapnoea may be bene \201 cial. Cardiovascular management may require invasive moni - toring to keep patients on the \200\230drier \200\231 side while avoiding complications. This will reduce pulmonary oedema and may help in reducing DAH. Many patients will develop acute renal failure and will thus require renal support. This may be temporary, but the ma jority of patients will require long-term RRT and will progress to end-stage renal disease. Sepsis must be aggressively treated, as one of the common complications of immunosuppressi ve therapy is infection. Adequate nutrition, tight control of blood sugar, DVT prophylaxis, etc. will be required in managing these patients. Management The mainstay of management is early and rapid identi \201 ca- tion of the vascu litic process and early treatment. The severity of disease dictates the intensity of initia l treatment, which in turn is often directly associated with risk of treat- ment-related co mplications such as sepsis. A combination of high dose corticosteroids and cyclo- phosphami de is the most commonly used \201 rst-line treat- ment for active generalized disease. Re mission in WG and MPA has been reported to be up to 90%; this may be less so in the critica lly ill . Trial of corticosteroids alone can be considered for CSS, PAN and conditions that are not immediately life threatening. Although both drugs are usu- ally given orally, in t he critically ill, the IV route is preferred as there may be uncertainty about gastric abso rption. There is evidence that pulsed IV cyclophosphamide is as effective in obtaining remi ssion as oral therapy and may be less toxic. For the patient in ICU with fulminant multi- s ystem disease, methylprednisolone is given IV in three daily doses (total daily dose of 0.2 5 \200\2231.0g) for 3 \200\2235 days followed by 1mg/kg oral prednisolone or equivalent. Cy clophosphamide (0.5 \200\2231g/m2 body surface area) IV is given at the same time and repea ted at 1 \200\2234 weekly inter- vals. Alternatively, 2 \200\2234mg/kg of oral cyclophospha mide is used, if gastric absorption is assured. Azathioprin may be substituted for cyclopho sphamide at 3 months to reduce complications of therapy. In addition to these therapies, pl asma exchange may be used, though its role is far from clear. Because of the com- plication s and morbidity associated with steroids and Conclusions Vasculitides are very rare in the ICU and have a high mortality. Delays in diag nosis of vasculitis in a previously undiagnosed patient are due to a number of factors, not the least because of the rarity of the condition in UK ICUs. Nevertheless, prompt diagnosi s is important for effective and aggressive therapy to be started. Unusual presentation, a high index of suspicion, detailed history and clinical examination along with serology in A NCA-associated vasculitides will speed the diagnostic process and start of therapy. Further reading Frankel SK, Cosgrove GP, Fischer A, et al. Update in the diagnosis and mana gement of pulmonary vasculitis. Chest 2006;129: 452 \200\22365. ICNARC case-mix program database. ICNARC, UK. 2007. Semple D, Keogh J, Forni L, et al. Clin ical review: vasculitis on the intensive care unit \200\224part 1: diagnosis. Crit Care 2004; 9: 92 \200\2237. Semple D, Keogh J, Forni L, et al. Clinical review: vasculitis on the intensive care unit \200\224part 2: treatment and prognosis. Crit Care 2004; 9: 193 \200\2237. Seo P, Stone J. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004; 117: 39 \200\22350. 472 A PITTARD Source control Abscess An abscess is a liquid- \201 lled collection containing a variety of cells walled off from surrounding healthy tissue. It may drain spontaneously, to form a sinus or \201 stula, or as a result of surgical or radiological intervention. Imaging by ultra- sound and CT are now both accurate and easy in compe- tent hands and can easily proceed immediately to percutaneous drainage if possible. This reduces the risk of contamination, avoids the ne ed for an operation and hence the complications associated with a surgical wound, e.g. woun d infection, dehiscence and pain control. The site of the collection and severity of illnes s of the patient will have some bearing on the method of control, e.g. an empyema can be id enti \201 ed with portable ultrasound and drained via a thoracostomy tube in the ward/ICU environment. More invasive radiological or surgical inter- vention will require transfer of the patient to another department with the additional risks that this entails. It is impor tant to consider unusual sources of infection includ- ing sinus and dental collections. Sou rce control is secondary to appropriate resuscitation measures, but may have to occur concu rrently and indeed may on occasion assist resuscitation. In dire circumstances where surgic al drainage is necessary, then use of a tempo- rary percutaneous drain could allow time for adequate resuscitation prior to de \201 nitive surgery. The source of infection may be fr om a perforated viscus. This is likely to be identi \201 ed clinically but aided by imagin g. Management will be in \202 uenced by the severity of illness of the patient, the availa ble surgical expertise and the site of the perforation. Options include: \200 The reported incidence of severe sepsis in critical care units varies between countries, e. g. 11.8 per 100 ICU admissions in New Zealand/Australia, 27.1 per 100 in the UK. Such patie nts have an increased LOS and a higher mortality. A signi \201 cant proportion of patients will be admit- ted because of their infection, whilst others will acquire it during their stay. Respiratory and abdominal infections are the most common cause of severe sepsis. Surg ery is not the only option when considering source control; the bene \201 t of any interve ntion must be balanced against the inherent risk of performing the procedure itself and any associated complications. Prophylaxis Prevention is better than cure \200\224 the following (not exhaustive) should a lways be considered: \200 \200 \200 Hand washing Aseptic technique Eradication therapy \200 \200 MRSA to prevent colonization Selective decontamination of the digestive tract (SDD) to redu ce risk of VAP \200 \200 Isolation of infected patients Closed suction of the respiratory tract Environment \200 \200 Microbiological surveillance Wall washing Damp dusting These are usually incorporated into local policy. Some are common sense, some have strong e vidence and some do not. Surgery; removal of the damaged viscus, e.g. appendi- cectomy Drain insertion A proximal, d efunctioning ostomy can be created Damage limitation surgery, i.e. doing the minimum to eli minate the source and allow recovery before return- ing for de \201 nitive treatment Treatment options Any infective process may fuel an in \202 ammatory response and may resu lt in severe sepsis and MOF. The source may be an abscess, necrotic tissue, contamination s econdary to a perforated viscus or an infected foreign body, e.g. in- dwelling catheter. In broad terms, source management may involve: \200 \200 \200 \200 \200 \200 Necrotic tissue Dead tissue is an ideal medium to support the growth of microorganisms. Deb ridement, if possible, is the optimal management, and timing is critical; however, there ar e also a variety of potential approaches in different circum- stances: \200 \200 \200 Antibiotics Surgical/percutaneous drainage Debridement Catheter removal Recent advances in imaging and interventional techniques frequently make percutaneous manag ement an option with a better risk \200\223bene \201 t pro \201 le. Surgery The use of special dressings Applying enzymatic or other biological agents Antibiotics The early use of appropriate antibiotics, i.e. within 1h of recognizing severe sepsis, is advised. This approach is asso- ciated with improved survival irrespective of wh ether infection is suspected or con \201 rmed (the Surviving Sepsis Campaign guidelines). It also helps with source control. A knowledge of the local ecology and resistance patterns is essential in antibiotic choice; a good working relationship with the microbiology depar tment is vital. Protocols may be in place but these need to evolve to \201 t the local ec ology. If non-stock antibiotics are needed, then mechanisms to allow them to be rapidly dis pensed from the drugstore will minimize delays in administration. Often a combination of the above is used. Typical radio- logical signs of necrosis will not always be evident, and in these circumstances, particularly when the patient is criti- cal ly ill, surgery is the only safe option. In most circumstances, debridement is not required imme- diately and therefore there will be time to resuscitate and stabilize the patient pr ior to surgery, e.g. debridement for necrotizing fasciitis should be performed within 12h, although as a general principle, the earlier the better. There are some situations where de lay is bene \201 cial and associ- ated with better outcome, e.g. allowing clear demarcatio n between healthy and necrotic tissue to develop, during which 473 CHAPTER 27.6 Source control Summary 1 Surveillance/prophylaxis 2 Early antibiotics/resuscitation 3 Source identi \201 cation \200 time hyperaemia in surrounding in \202 amed tissue will reduce so there is less bleeding d uring surgery. It is for this reason that delayed pancreatic necrosectomy is associated wit h a better outcome. The use of continuous peritoneal lavage may remove con- taminated tissu e and and reduce the risk of recurrent infection. Planned re-laparotomy can be facilitated by adopting an \200\230open abdomen \200\231 technique where mesh or another material is u sed to cover the defect temporarily. This avoids the risks associated with raised intra-abd ominal pressure but can expose the patient to further infection and is labor intensive to m anage. Imaging will depend on suspected site and severity of illness of patient. Seek advice from radiologist If collection identi \201 ed, need to identify underlying cause. May require c ontrast studies 3 Source control \200 Collection should be drained (percutaneous or surgical) Perforated viscus could be removed or defunctioned Extensive debridement within 12h of diagnosing necro- tizing fasciitis Cons ervative/supportive management and/or peritoneal lavage if pancreatic necrosis Consider sur gery if negative imaging con \201 rmed by sen- ior radiologist, dead tissue suspected as u nderlying cause and patient critically ill Only change invasive lines when they are suspect ed as the underlying cause or there is evidence of infection, e.g. in \202 amed/purulent e ntry site \200 Infected foreign body The most common infected foreign body in ICU is the in- dwelling CVC. It always makes sense to remove an infected object. Occasionally this is not possible, e.g . endocarditis in a prosthetic valve. When an in-dwelling vascular catheter is suspected as a source of infection, blood cultures should be taken from the line and via a peripheral s tab. A new site is best, but if this is problematic then an infected line can safely be cha nged over a guide wire unless there is infection or in \202 ammation around the entry site . Local guidelines should be followed. Tunneled lines are less likely to become infected, a nd soft tissue infection can be managed with appropriate antibiotics. There is debate as to when lines should be changed. Venous catheters should only be changed when there is eviden ce of infection. Further reading Jimenez MF, Marshall JC. Source control in the managament of sepsis. Intensive Care Med 2001; 27: S49 \200\22362. Kunar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit C are Med 2006; 34: 1589 \200\22396. 474 DF ZANDSTRA & HKF VAN SAENE Selective decontamination of the digestive tract (SDD) Philosophy The key to SDD for infection control in the ICU is to consider that there are th ree different types of infection due to a limited range, 15 PPM, of potentially pathogenic microorganisms (PPMs): 6 \200\230normal \200\231 and 9 \200\230abnormal \200\231 organ- i sms. Each requires a different prophylactic maneuver. \200 Antimicrobial resistance as a long-term issue in SDD has been investigated in 11 studies ov er periods varying between 2 and 9 years, and bacterial resistance associated with SDD has not been a clinical problem. Practical guidelines: how to do SDD All ICU patients requiring \211 2 days of mechanical v entila- tion are given, on admission, parenteral cefotaxime in high doses, for 4 days. This targets mortality due to \200\230early \200\231 pri- mary endogenous infections \200\224 \200\230normal \200\231 PPMs such as S. pneumoniae and S. aureus (See Table 27.7.3) Enteral antimicrobials are given throughout the treatment on ICU to control mortality associated w ith \200\230late \200\231 secondary endogenous infections. A paste or gel is applied into the oropharynx to prevent or eradicate oral carriage of \200\230abnormal \200\231 PPMs, in the oropharynx. A suspension is administered via the NG tube to decontaminate stomach and gut. Polymyxin and tobramycin are used to control carriage of \200\230abnormal \200\231 Gr am-negative bacteria, in particular Pseudomonas aeruginosa. Enteral vancomycin is added to polymyxin/tobramycin in the case of MRSA endemicity. Enteral amphotericin B or nystatin is used to control yeast overgrowth. \200\230Exogenous \200\231 infections should be prevente d by hygiene measures. Regular surveillance cultures of throat and rectum are obtained to m onitor ef \201 cacy and safety of the enteral anti- microbials. Exogenous infections are controlled by a high level of hygiene Primary endogenous infection s are controlled by the immediate administration of parenteral antibiotics. Secondary endog enous infections are controlled by the application of enteral antimicrobials in the throat and gut (See Table 27.7.1). The terminology Primary endogenous: infections caused by pathogens present on admission Sec ondary endogenous: infections caused by pathogens not present on admission, but developing after acquired colonization in ICU Exogenous: infections caused by pathogens not present on admission and developing without preceding colonization De \201 nition SDD is a prophylactic protocol using hygiene, paren- teral and enteral anti microbials which aims to control exogenous, and primary and secondary endogenous infections , due to the 15 PPMs and hence reduce mortality. Ef \201 cacy There are 56 RCTs and 13 meta-analyzes assessing the ef \201 - cacy of SDD. SDD reduces the OR for lower airway and bloodstream infections to 0.35 (95% con \201 dence interval 0.29 \200\2230.41) and to 0.63 (95% CI 0.46 \200\2230.87), respectively. SDD has the following effects. 1 Signi \201 cantly reduces carriage and infection due to aerobic SDD and evidence-based medicine Five ICU interventions have been shown convincingly to redu ce mortality (RCTs). SDD has grade A recommendation and can be applied in all patients requ iring long-term intensive care. It addresses the ever-increasing resistance problem. The sa me cannot be said for low tidal volume, APC, intensive insulin and steroids which have only been evaluated in speci \201 c subsets of ICU patients. Gram-negative bacilli and yeasts (See Table 27.7.2). 2 Reduces Gram-positive lower airway infections (OR Conclusion SDD is an evidence-based medical maneuver using parenteral and enteral antimicro bials which reduces morbidity by 65% and mortality by 29%. It is not associated with antimi crobial resistance emerging in unselected criti- cally ill patients. It is a prophylactic m ethod that costs 6 Euros a day. 0.52; 95% CI 0.34 \200\2230.78). 3 Does not reduce carriage due to Gram-positive bacteria (i.e. not signi \201 cant). 4 Does not increase gram-positive bloodstream infections (OR 1.03; 95% CI 0.75 \200\2231.41). 5 Does not signi \201 cantly reduce fungaemia (OR 0.89, 95% CI 0.16 \200\2234.95), due to the low event rate. Further Reading Brun-buisson C, Legrand P, Rauss A, et al. Intestinal decontamina- tion for control of multi-resistant Gram-negative bacilli. Ann Intern Med 1989; 110: 873 \200\22381 . The most recent mortality meta-analysis including 4755 patients from 22 RCTs demonstrates t hat SDD reduces the OR for mortality to 0.71 (0.62 \200\2230.82) (See Table 27.7.2). Safety SDD does not increase the problem of antimicrobial resist- ance but rather solves th e antibiotic resistance problem. An RCT of 1000 patients reported that carriage of aerobic Gram-negative bacteria (AGNB) resistant to imipenem, ceftazidime, ciprofloxacin, tobramycin and polymyxins occurred in 16% of patients receiving parenteral and enteral antimicrobials , compared with 26% of control patients receiving only parenteral antibiotics with an RR of 0.6 (95% CI 0.5 \200\2230.8). Liberati A, D \200\230Amico R, Pifferi S, et al. Antibiotic prophylaxis to reduce respirato ry tract infections and mortality in adults receiving intensive care. Cochrane Database Sys t Rev 2004; (1): CD000022. Silvestri L, van Saene HKF. Survival bene \201 t of the full digestive decontamination reg imen. Systematic review of randomized con- trolled trials. J Crit Care 2008, in press. Silvestri L, van Saene HKF, Casarin A, et al. Impact of selec tive decontamination of the d igestive tract on carriage and infection due to Gram-negative and Gram-positive bacteria: a system atic review of randomized controlled trials. Anaesth Intensive Care, 2008; 36, 324 \200\22338. 475 CHAPTER 27.7 Selective decontamination of the digestive tract (SDD) Silvestri L, van Saene HKF, Milanese M, et al. Impact of selective decontamination of the d igestive tract on fungal carriage and infection: systematic review of randomized controlled trials. Intensive Care Med 2005; 31: 898 \200\223910. van Saene HKF, Silvestri L, de la Cal MA, et al. Selective decontami- nation of the digesti ve tract reduces lower airway and blood stream infection and mortality and prevents emergen ce of anti- microbial resistance. Microbes Infect 2006; 8: 953 \200\2234. Silvestri L, van Saene HKF, Milanese M, et al. Selective deconta- mination of the digestive tract reduces bacterial bloodstream infections and mortality in critically ill patients. S ystematic review of randomized controlled trials. J Hosp Infect 2007; 65, 187 \200\223203. Table 27.7.1 Control of nosocomial infection Infection PPM Timing Frequency Maneuver 1. Prim endog 6 \200\230normal \200\231 9 \200\230abnormal \200\231 <1 week 55% Parenteral antimicrobials 2. Sec endog 9 \200\230abnormal \200\231 >1 week 30% Enteral antimicrobials 3. Exogenous 9 \200\230abnormal \200\231 Any time during ICU treatment 15% Hygiene 4. Monitoring ef \201 cacy/safety prophylaxis Surveillance cultures Throat/rectum PPM = potentially pathogenic microorganisms; Prim endog = primary endogenous; Sec endog = s econdary endogenous. 6 \200\230normal \200\231 PPM are Streptococcus pneumoniae, Haemophilus in \202 uenzae, M oraxella catarrhalis, Candida albicans, Staphylococcus aureus, Escherichia coli 9 \200\230abnormal \200\231 PPM are Klebsiella, Proteus, Morganella, Enterobacter, Citroba cter, Serratia, Acinetobacter, Pseudomonas species and MRSA. Table 27.7.2 Impact of SDD on carriage/infection due to Gram \200\223ve, Gram +ve bacteria and yeasts PPM Type of patient Sample size Carriage OR (95% CI) Overall infection OR (95% CI) Gram \200\223ve All 9473 O. 0.13 (0.07 \200\2230.23) R. 0.15 (0.07 \200\2230.31) 0.17 (0.10 \200\2230.28) Gram +ve All 9473 O. 0.55 (6.30 \200\2231.02) R. 0.53 (0.12 \200\2232.43) 0.76 (0.41 \200\2231.40) Yeasts All 6075 0.32 (0.19 \200\2230.53) 0.30 (0.17 \200\2230.53) PPM = potentially pathogenic microorganisms; O. = oropharyngeal; R. = rectal. Table 27.7.3 Full four-component protocol of SDD Target PPM and antimicrobials Total daily dose (4 \227 daily) <5yrs 5 \200\22312yrs >12yrs 1. Enteral antimicrobials: \200\230abnormal \200\231 PPM A. Ooropharynx AGNB: polymyxin E with tobramycin Yeasts: amphotericin B or nystatin MRSA: vancomycin 2 g of 2% paste or gel 2 g of 2% paste or gel 2 g of 4% paste or gel 2 g of 2% paste or gel 2 g of 2% paste or gel 2 g of 4% paste or gel 2 g of 2% paste or gel 2 g of 2% paste or gel 2 g of 4% paste or gel B. Gut AGNB: polymyxin E (mg) with tobramycin (mg) Yeasts : amphotericin B (mg) or nystatin (units) MRSA: vancomycin (mg) 100 80 500 2 \227 106 20 \200\22340/kg 200 160 1000 4 \227 106 20 \200\22340/kg 400 320 2000 8 \227 106 500 \200\2232000 2. Parenteral antimicrobials: \200\230normal \200\231 PPM cefotaxime (mg) 150/kg 200/kg 4000 3. Hygiene 4. Surveillance cultures of throat and rectum on admission, Monday, Thursday 476 G MARX & K REINHART Markers of infection \200 Tips of in-dwelling catheters. Microbiological investigation of any drainage fluid availabl e. Radiological investigation (CXR or a CT scan) searching a focus. Echocardiogram to exclu de endocarditis. Dental status excluding an odontogenous focus. The diagnosis of infection in the ICU patient may be obvi- ous or extremely dif \201 cult. Infection, and especially sepsis, is a leading cause of death and the main cost driver in ICUs. Epidemiologic data show that sepsis is the third most fre- quent cause of death after coronary heart disease and MI in Germany. The \201 rst clinical signs of infection or se psis are usually non-speci \201 c (e.g. fever or leucocytosis). More speci \201 c symptom s, such as arterial hypotension or raised lactate, often indicate progression to organ dysf unction associated with an increased mortality rate of 35 \200\22370%. The ideal infection/ sepsis marker has high sensitivity and speci \201 city, easy handling and low costs. The m arker should be able to indicate the stages of the disease and the prog- nosis of the patie nt. The in \202 ammatory reaction consists of humoral, cellular and molecular pathways. Ch anges in body temperature, leucocyte count, heart rate, blood pressure and respiration rate are clinical signs of systemic in \202 ammation. They are neither speci \201 c nor sensi tive for sepsis and also occur in non-infectious states. Generalized in \202 ammation with organ dysfunction (systemic in \202 ammatory response syndrome) may also result from panc reatitis, major trauma and burns. The American College of Chest Physicians/Society of Criti cal Care Medicine consensus criteria are not helpful for clinical differentiation at the be dside. Ideally, an infec- tion marker should meet the following demands: 1 Shorten the time to and accuracy of diagnosis 2 Facilitate the differentiation between infectious and non- infectious causes of in \202 ammation and its sequelae \200\224 organ dysfunction or shock \200 Special investigations \200 Procalcitonin (PCT): bacterial endotoxins are a major stimulus for PCT induction, but Gram- positive infections may also induce a PCT release and may be detected within 2h of endotoxa emia or bacteraemia. During severe fungal infections, PCT induction has been described in s ome patients. However, major surgery, severe trauma or burns may also induce an increase of PCT plasma levels, although usually not as high as in patients with severe sepsis or septi c shock. A number of studies con \201 rm PCT as a marker of severe infections and sepsis. Those with PCT levels \211 0.5ng/ml are unlikely to have severe sepsis or septic shock, wh ereas levels >2ng/ml identify patients at high risk. PCT concentra- tions >10ng/ml usually occur in patients with organ fail- ure remote from the site of infection. When PCT is relea sed non-speci \201 cally because of major surgery or severe trauma, daily monitoring may b e helpful to detect supervening septic complications early. CRP is an acute-phase protein t hat is released from hepatic cells after stimulation by in \202 ammatory media- tors such as IL-6 and IL-8. The value of high plasma levels of CRP in diagnosing patients with infect ion and sepsis or the assessment of sepsis severity is controversial. CRP may not peak not till 48h. Circulating CRP increases dur- ing minor infections, does not correlate with the severity of host response and does not differentiate between survivors and non-survivors of sepsis. CRP plasma levels may remain elevated up to several days, and it is found in many non-infectious conditions, such as autoimmune and rheumatic disorders, ACS and malignant tu mors, and after surgery. Endotoxin (LPS) is an essential structure in the outer cell membra ne of Gram-negative bacteria. The Limulus amoebocyte lysate assay was problematic, with wid e variation in value, low speci \201 city (due to differences in the endotoxin structure i n different bacteria) and interactions with plasma proteins and antibiotics. A new highly s ensitive ex vivo biological assay will soon be available. It measures the zymosan antibody- and antien- dotoxin antibody-elicited respiratory burst in a kinetic luminometric assay. I t has a high negative predictive value for the diagnosis of Gram-negative infection and sep sis, with a sensitivity of 85.3% and a speci \201 city of 44%. The endotoxin activity essa y has promise for Gram-negative infection. 3 Allow differentiation between underlying viral and bac- terial infections 4 Re \202 ect the effectiveness of antimicrobial treatment and other measures of source co ntrol more accurately than conventional clinical and laboratory signs. Clinical approach Once infection is suspected in the ICU patient, the goal is to identify t he infecting pathogen. History: key points \200 Past medical history to identify previous infections and co-morbidities) recently used anti microbial therapy, recent medical interventions or the risk for colonization/ infection wit h resistant organisms. Mental state. Septic encephalopathy is one of the most commonly miss ed initial signs of an infection. Examination and investigation: key points \200 Clinical opinion to con \201 rm diagnosis by measuring tem- perature, respiratory rate, he art rate and blood pressure, examination of CNS, thorax, heart, lung, abdomen, kidney or an y other susceptible area. FBC to measure the WCC. Blood specimen (2 \200\2233 blood aerobic and anaerobic cultures). Urine specimen to exclude UTI. Bronchoalveolar lavage (BAL) or tr acheal secretions and direct examination of BAL specimen using Gram staining for the diagno sis of pneumonia. Feces in the presence of diarrhea, Other specimen (CSF, exudates, swabs o f mucous membranes). \200 Clinical diagnostic dif \201 culties to consider In sepsis, blood cultures are positive in 30 \200\22340% of those with sepsis and with false positives. Positive results may indica te colonization or contamination without pathophys- iological relevance. Microbiological di agnosis may be dif \201 - cult in patients with prior antibiotic treatment. In 35%, sepsis cannot be proved microbiologically despite the pres- ence of clinical signs and suspicion of a focus. \200 \200 477 CHAPTER 27.8 Markers of infection Diagnosis of special infections Ventilator-associated pneumonia The diagnosis of VAP is dif \201 cult since there is no accurate diagnostic criterion which reliably differentiates p neumo- nia from non-infectious causes of pulmonary in \201 ltration. Interpretation of mic robiological \201 ndings is hampered by the high rate of colonization in mechanically ven tilated patients. The International Sepsis Forum recommends the use of the Clinical Pulmona ry Infection Score (CPIS) for the diagnosis of VAP (CPIS >6). The score is based on body te mperature, WCC, volume and appearance of tracheal secretions, oxygenation (PAO2/FIO2), CXR and tracheal aspirate cultures. The CPIS allows for a standardized diag- nosis by using sim ple clinical end-points. In a clinical study, the CPIS was able to diagnose pneumonia with a sensitivity of 93% and a speci \201 city of 100%.