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. During insertion the use of maximal sterile barriers including a sterile gown, sterile glov es and a large sterile drape reduces CR-BSIs. The skin should be cleansed with alcoholic ch lorhexidine gluconate solution or with povodine-iodine if patients are sensitive to chlorhe xidine. Single lumen catheters should be used unless multiple ports are essential for patie nt management, and a dedi- cated lumen should be kept exclusively for parenteral nutrition. A tunneled line or implantable device should be used if vascular access is required for >3 \200\2234 weeks. Antimicrobial- or silver-impregnated lines are available and may be appro priate in patients requiring short-term central venous access and who are at high risk of C R-BSI, in situations where rates of CR-BSI remain high despite strategies to reduce them. I nsertion of the line into a subclavian site appears to be associated with lower rates of in fection than femoral or internal jugular sites, and should be used unless medi- cally contr aindicated. Central lines should not be replaced routinely but on evidence of infection. If a patient has a CR-BSI, then guide wire-assisted exchange should not be used for line repl acement. Local antibiotic policy In ICU, the aim is to use the safest, most effective (and most econ omical) antimicrobials whilst reducing the risk of selection of bacterial resistance. Local antibiotic policies should be developed in collaboration by clinicians, micro- biologists and pharmacists, and be regularly reviewed. They are based on the nature of the local patie nt population and must re \202 ect the types and susceptibility patterns of patho- gens ci rculating within the ICU, the hospital and the local community. The implementation of antib iotic guidelines has been asso- ciated with stable antibiotic susceptibility patterns for G ram-negative and Gram-positive organisms. The use of narrow-spectrum antibiotics appears to be associated with lower resistance rates and fewer episodes of antibiotic- associated dia rrhea due to Clostridium dif \201 cile. Restricted use of speci \201 c antibiotics or ant ibiotic classes in association with other infection control measures have been used to halt outbreaks of antibiotic-resistant bacteria. Studies can be found to support and refute the bene \201 ts of antibiotic cycling, and it may be that antibiotic heterogeneity, achieved by \200\230mixing \200\231 antibiotics is more effective. Prevention of transmission of infection Hospital environmental hygiene The most important s ource of transmitted infection is the hands of health workers, but almost every item of equ ipment in the ICU has been shown to be a source of nosocomial infection. The environment mu st be kept clean, and surfaces Ventilator-associated pneumonia Nosocomial pneumonia has mortality rates of 20 \200\22350%. VAP rates can be reduced by methods to prevent aspira- tion, such as elevation of the pati ent \200\231s head to a 30 \200\22345 465 CHAPTER 27.2 Infection control \200\224general principles Screening for these organisms on admission to ICU is important to provide appropriate isola tion or cohorting of colonized patients. Up to 86% of VRE or MRSA-colonized patients will n ot be recognized except by active surveil- lance. New very rapid (hours) techniques are bec oming available for screening. damp-dusted at least daily. Routine use of disinfectants is not necessary, but disinfection of isolation rooms or areas where patients with multi-resistant organisms have been nursed should be carried out as per local infection control recommendations. Hand hygiene Despite the hands being the most common vector for spread of infection, compli ance rates of ICU hand washing procedures average 30 \200\22340%. Rates can be improved wit h the use of hand disinfection with alcohol-based antiseptic hand rubs which are highly eff ective and quicker to use. Hands that are visibly soiled should be washed in soap and water . Hand washing is more effective against certain diar- rhoeal pathogens such as Norovirus a nd the spores of C. dif \201 cile. Hygienic hand wash refers to washing hands with an anti septic agent added to the detergent, and should be used when prolonged reduction in microbi al \202 ora on the hands is required, such as before invasive procedures. Improvement in infection rates has been shown in response to improved hand hygiene compliance in descripti ve stud- ies and clinical trials. Consult infection control team The infection control team \200 \200 \200 \200 policy production education of staff practical advice audit in close collaboration with ICU staff. Surveillance is an essential part of prevention and control. It helps to detect and de \201 ne sources of cross-infection more rapidly and to evaluate control methods, and pro- v ides information for resource allocation in infection con- trol. There are various ways thi s may be achieved, but surveillance is best conducted prospectively by staff trained in inf ection control. Staf \201 ng The strict application of barrier nursing techniques in ICU may break down du ring periods of understaf \201 ng or over- crowding, and this has been associated with out breaks of nosocomial infection. Personal protective equipment Appropriate use of aprons, gowns, gloves, protective eye- wea r and face masks protects staff and prevents transmis- sion of microorganisms to patients. In the ICU, disposable gowns/aprons and gloves should be used for each patient care episode . Gloves must be discarded and hands decon- taminated after each care activity for a patien t. Particulate \201 lter masks are worn when caring for patients with respi- ratory infec tions transmitted by airborne particles, such as Mycobacterium tuberculosis or epidemic in \202 uenza. Face masks and eye protection protect mucous membranes from splashes. Face mas ks have not been shown to protect patients from healthcare-associated infection during rou- tine ward procedures. There are concerns, however, about the \200\230cloud \200\231 healt hcare provider phenomenon whereby viral upper respiratory tract infection promotes transmis sion of pathogens such as MRSA which colonize the oropharynx. Some of this transmission may be prevented by face masks, although healthcare workers may provide better protec- tion to their patients by staying away from work when unwell themselves. Occupational health Staff should be up to date with vaccinations for hepatitis B, TB, in \202 uenza and varicella-zoster. Measles status is increas- ingly important. Further reading Emmerson AM, Enstone JE, Grif \201 n M, et al. The Second National Prevale nce Survey of infection in hospitals \200\224overview of the results. J Hosp Infect 199; 32 : 175 \200\22390. Fagon JY, Chastre J, Wolff M, et al. Invasive and noninvasive strate- gies for management o f suspected ventilator-associated pneumo- nia. A randomized trial. Ann Intern Med 2000; 132 : 621 \200\22330. Kollef MH. Is antibiotic cycling the answer to preventing the emer- gence of bacterial resi stance in the Intensive Care Unit? Clin Infect Dis 2006; 43 Suppl 2: S82 \200\2238. Molstad S, Cars O. Major change in the use of antibiotics following a national program: Swe dish Strategic Program for the Rational Use of Antimicrobial Agents and Surveillance of Res istance (STRAMA). Scand J Infect Dis 1999; 31: 191 \200\2235. Contact precautions/isolation Two types of isolation (or barrier nursing) are used in the I CU setting: \200\230protective \200\231 or \200\230source \200\231. Immunocompromised pat ients need protective isolation from pathogens circulat- ing in ICU. Patients with communic able diseases or carry- ing multi-resistant bacteria are cared for in source isolation to p rotect other patients and staff from acquiring these pathogens. If isolation facilities are not available, other options of providing contact precaution may be used, such as cohortin g. Although not an exhaustive list, some of the organisms that should prompt isolation incl ude MRSA, C. dif \201 cile, vancomycin-resistant Enterococcus (VRE) and multi-resistant Gr am-negative bacteria such as multi- resistant Acinetobacter baumanii. Patients may be colon ized with multi-resistant organisms but not manifest active infection, and so may not be re cognized. Pearson ML. Hospital Infection Control Practices Advisory Committee. Guideline for the prev ention of intravascular-device- related infections. Infect Control Hosp Epidemiol 1996; 17: 438 \200\22373. Pittet D. Improving adherence to hand hygiene practice: a multidis- ciplinary approach. Emerg Infect Dis 2001; 7: 234 \200\22340. Pratt RJ, Pellowe CM, Wilson JA, et al. epic2: national evidence-based guidelines for preve nting healthcare-associated infections in NHS hospitals in England. J Hosp Infect 2007; 65 Suppl 1: S1 \200\22364. Salgado CD, O \200\231Grady N, Farr BM. Prevention and control of antimi- crobial-resistant infections in intensive care patients. Crit Care Med 2005; 33: 2373 \200\22382. Sherertz RJ, Bassetti S, Bassetti-Wyss S. \200\230Cloud \200\231 health-care workers. Emerg Infect Dis 2001; 7: 241 \200\2234. 466 R JONES AND M NELSON HIV In general, in individuals with non-HIV-related conditions and a CD4 count >200 cells/mm3, ARV therapy can be deferred, as outcome will be related to the resolution of the non-HIV-re lated condition. In those admitted with an AIDS-de \201 ning illness or with a CD4 count < 200 cells/mm3, prophylaxis against opportunistic infections and, where appropriate, ARVs sh ould be considered. If the individual develops IRIS, ARVs are usually continued. Corticoste roid therapy may be required. Since the \201 rst description of the HIV immunode \201 ciency syndrome in 1981, the pro gnosis for individuals living with HIV infection in the Western world has transformed. In t he early years of the epidemic, survival was <10yrs and the emphasis focused on palliative care. Now, however, most of the population living with HIV will survive for many years, pro viding they are able to access and adhere to highly active antiretroviral therapy (HAART). Previously, there had been a reticence to transfer individuals with HIV to more intensive/c ritical care settings due to the relatively poor clinical outcome. Admissions were often co stly and unsuccessful. In the HAART era, with improvements in knowledge and management of H IV, this reticence has diminished. Pneumocystis jirovecci pneumonia (PCP) Historically, the most common reason for HIV-related critical care has been respiratory failure. Whilst bacterial pneumonia and TB are importan t causes of compromise in this population, PCP remains a major cause of morbidity, often re quiring assisted ventilation. These patients are prone to pneumothorax, especially if pneum atocoeles are present, and ventilatory measures should be considered with care. The care of HIV patients This should be provided by a multi-disciplinary team. Critical car e provision should be no exception. Prescription of HAART may be complicated by factors inc luding HIV resistance, drug administration and pharmacokinetics; thus, antiretroviral (ARV) regimens should not be altered with- out the advice of an HIV clinician and pharmacist. In areas where there is no direct access to a specialist HIV team, a network should exist to enable units to seek advice and support from a designated HIV center. As the prognosis for individuals living with HIV has improved, increasingly patients are affected by non-HIV co- morbidities including cardiovascular, hepatitis and chronic conditions, e.g. emphysema. The predominance of oncological diagnoses especially non-Hodgkins lymphoma in this population, and the subsequent chemotherapeutic regimens (which may be dif \201 cult to construct in the pres- ence of HAART) may predispose to neutropenic sepsis, often requiring critical car e support. The management of these conditions should not differ from that of the HIV-negati ve population. Within this chapter, we discuss the general management of HIV-infected indiv iduals in the critical care setting, focusing upon opportunistic infections. Presentation Typically, dry cough, increasing dyspnoea and pyrexia. There may be few or no chest signs despite signi \201 cant disease. Investigation CXR may be normal in up to 50% of individuals, or show perihilar shadowing wi th diffuse interstitial in \201 ltration \200\224 \200\230ground glass \200\231 shadowing . Pneumothoraces may be present. ABG indicates the disease severity and guides manage- ment . In the less sick, exercise oximetry is useful, and a drop in oxygen saturation to <90% af ter 10min on an exer- cise bicycle is suggestive of PCP. Induced sputum should be sent. If negative, consider bronchoscopy. Treatment If PaO2 <8kPa, commence IV methyl prednisolone 40mg qds. First-line therapy is IV co-trimoxazole 3840mg bd (unless <60kg when dose should be adjusted to 60mg/kg bd) for 14 \200\22321 days. Side effects of nausea are commonm and pre-emptive antiemetics should be p rescribed. Rash, bone marrow suppression (BMS), hepatotoxicty and neph- rotoxocity may be o bserved. Monitor FBC, U&E and LFTs closely. Second-line therapy, instigated due to side eff ects or failure, comprises IV/oral clindamycin 600mg qds and oral primaquine 300mg od. Clin damycin is linked to diarrhoeal episodes (exclude Clostridium dif \201 cile) and hepatotox icity. Primaquine may cause nausea, methaemaglobinaemia, haemolytic anemia and BMS. Again, monitor bloods. Alternative agents include dapsone and trimethiprim, pen- tamadine and atov aquone Secondary prophylaxis is required post-treatment. HIV testing in the critical care setting A signi \201 cant proportion of individuals admit ted to the CCU/ICU are unaware of their HIV status. Obtaining informed consent is often imp ossible. HIV tests are often performed in \200\230the patients \200\231 best interests \200\231. In practice, there are few situations where an HIV test result will alter a patie nt \200\231s immediate management but, where it may, testing should be performed. Low CD4 c ounts are often seen in the critically ill, irrespective of HIV status. Antiretroviral therapy in the critically ill patient There is limited information about the introduction of HAART in the ITU setting. There is concern regarding the immune reconstitu tion in \202 ammatory syndrome (IRIS), a paradoxical worsening of an individual \200\231s clinical state as the immune system is restored. HAART administration is dif \201 cult as Zidovudine (AZT) is the only ARV available in IV form, and NG administration of ARVs may le ad to inade- quate plasma levels, fueling the accumulation of HIV resist- ance. Drug intera ctions are common, e.g., co-administration of the protease inhibitor, atazanavir with antac ids signi \201 - cantly reduces its plasma level. Renal or hepatic insuf \201 - ciency ma y also contraindicate the use of ARVs. Cryptococcal meningitis Presentation Classically, headache and pyrexia. Meningism is presen t in <30%. Investigation Negative serum cryptococcal antigen (CrAg) excludes the diagnosis. Following a CT head, urgent LP, including meas- urement of CSF opening pressure (OP), should be per- formed. If the OP is >20cm H2O, CSF should be drained until the OP is below this level. Dai ly LPs may be required, and a ventriculoperitoneal shunt may be necessary. CSF CrAg is posi tive in cryptococcal meningitis. Negative CSF 467 CHAPTER 27.3 HIV radiological and clinical improvement following 2 weeks of speci \201 c antitoxoplasmosis therapy. CrAg, with positive serum CrAg, indicates cryptococcosis, and individuals should be treated with \202 uconazole to pre- vent meningitis. Indicators of a poor prognosis include rais ed ICP, decreased level of consciousness, CSF CrAg 1:1024, low CSF WCC and positive serum c ryptococcal culture. Investigation Negative serology (titre <1:16) implies that toxoplasmosis is unlikely but no t impossible. Raised titres or presence of IgM are not diagnostic of acute infection, but i ndicate reac- tivation potential. MRI brain scan should be performed, classically revealing characteristic multiple ring enhancing lesions. Space-occupying lesions may preclude LP. I f per- formed, results are often normal, or a slight elevation of protein mononuclear pl eocytosis may be seen. Treatment First-line therapy is IV amphotericin B. Give a test dose of 1mg in 100ml of norm al saline and monitor for adverse events. Systemic symptoms such as fever, chills, myalgia and headache may occur. Chlorpheniramine 10mg IV, paraceta- mol and hydrocortisone 25 \200 \22350mg IV given pre-emptively may alleviate these symptoms. Initial treatment is ampho- t ericin 250mcg/kg/day following the test dose. Further side effects include nephrotoxicity, hypokalaemia, hypomagne- saemia, hepatotoxicity and thrombophlebitis. Again, blood paramete rs, including calcium and magnesium, should be monitored closely. Amphocil may be required in cases of nephrotoxicity. The use of additional \202 ucytosine is contro- versial. Alth ough there is a faster rate of CSF sterilization, this does not translate into a survival a dvantage, and the additional toxicity of \202 ucytosine may not be warranted. Second-line therapy is comprised of \202 uconazole with or wiithout flucytosine. Secondary prophylax is will be required following treatment. Treatment Oral/IV sulfadiazine 2g qds (if patient weighs >70kg) with oral pyrimethamine 75m g od and oral folinic acid 15mg od support. Side effects include nausea, vomiting, rash, cr ystalluria, hepatotoxicity and BMS. Monitor bloods closely. Second-line therapy is oral cli ndamycin 600mg qds, oral pyrimethamine 75mg od and oral folinic acid 75mg od. Adverse event s include rash, hepatotoxicity and BMS. Approximately 80% of patients should respond to ant i- Toxoplasma treatment. The majority will experience a radiological and clinical improveme nt within 14 days. Further reading Gottlieb M, Schroff R, Schanker H, et al. Pneumocystis carinii pneu- monia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired ce llular de \201 ciency. N Engl J Med 1981; 305: 1425 \200\22331. Toxoplasmosis encephalitis Presentation Commonly headache, pyrexia, confusion focal neur ology. The main differential diagnosis is primary cerebral lymphoma. In practice, diagnosis is often retrospective, indicated by a Keiser O, Taffe P, Zwahlen M, et al. All cause mortality in the Swiss HIV Cohort Study from 1990 to 2001 in comparison with the Swiss population. AIDS 2004; 18: 1835 \200\22343. 468 G BELLINGAN & J SCHOUTEN Severe falciparum malaria An estimated 300 \200\223500 million people contract malaria annually and 1.5 \200\2232.7 m illion die. Global travel has contrib- uted to the increased incidence of imported malaria in developed countries, and the impact is compounded by the increasing incidence of drug-re sistant Plasmodium falci- parum malaria. Malaria is caused by obligate intraerythro- cytic protozoa that are primarily transmitted by the infected female Anopheles mosquito. Although quinine is the current gold standard, artemisinin- based regimens may be better. S tudies in Asia suggest that artemisinin derivatives reduce the mortality (15 vs 22%) in adu lts with severe malaria compared with quinine. Artesunate is well tolerated. Equivalent stu dies with artesunate from Africa are currently lacking, and good quality IV artesunate is u navailable or in short supply in many Western countries (IV artesunate is unlicensed in the EU), so quinine is often still used. Certainly quinine-resistant P. falciparum requiring I V therapy should be treated with IV artemisinin combined with tetracycline or me \202 oqui ne. If artemisinin is not available, IV quinine or quinidine plus tetracycline or doxycycli ne should be given. Diagnosis Malaria must always be suspected in any patient with unex- plained fever or clini cal deterioration who has returned from an endemic area within the past few years. The risk of severe falciparum malaria developing is greatest among young children and visitors (of any age) from non-endemic areas. There are four types of malarial parasite affecting man; h owever, severe malaria is caused almost invariably by P. falciparum infection. Patients are considered to have severe malaria if they have one or more of the underlying features: \200 \200 \200 \200 \200 \200 \200 Supportive measures Patients with severe falciparum malaria must be admitted to HDU/ICU for full monitoring, including heart and blood glucose. If hypotension and hypoxaemia develop, then, as with all septic patients, appropriate \201 lling guided by moni- toring the card iovascular state, stroke volume and mixed venous saturations should be undertaken. After ea rly resuscitation ( \201 rst 48h), a positive \202 uid balance should be avoided for any patients with ALI/ARDS. Intubation and mechanical ventilation may be indicated not only in those with respiratory failure but also as part of airway protec- tion for cerebral malari a to prevent hypercapnia and a subsequent rise in ICP. An LP should be performed in comatos e patients to exclude bacterial meningitis. The OP is usually normal in adults; CSF is clea r, with <10 white cells/ l and the protein is often slightly raised. Malaria itself is onl y associated with mild neck stiffness; neck rigidity and photophobia are absent. Other asso ciated or nosocomial infections should also be looked for and treated; these are not uncomm on and can lead to a picture of sepsis; shock can occur in malaria but is more often due to secondary infection. Cerebral malaria is particularly serious but can resolve with support and treatment, although recovery can be slow. Convulsions and retinal hemorrhages are comm on; papilloedema is rare. A variety of transient abnormalities of eye movement, especially disconjugate gaze, may occur. Convulsions should be treated with diazepam. An NG tube shoul d be inserted and the stomach aspirated unless airway protection has been secured. Renal fa ilure (usually oliguric) is virtually con \201 ned to adults. The mechanisms underlying re nal failure are not well understood, although it is usually reversible. The old fash- ioned \200\230blackwater fever \200\231 with severe haemolosysis is now very uncommon. Treatmen t is supportive, maintaining a good \202 uid balance, ensuring no evidence of obstruc- ti on and commencement of haemo \201 ltration if required. Hypoglycaemia is common and should be treated with 50% dextrose followed by a continuous infusion of dextrose, if required. M ost patients can be established on eneteral nutrition early, and should be maintained on a regimen of tight glycaemic control. A very common \201 nding is a low platelet count, usu ally without any bleeding. This typically recovers as the parasite count falls. DIC is unco mmon. A parasitemia of >5% Altered consciousness Oliguria Jaundice Severe normocytic anemia Hypog lycaemia Organ failure In addition to the features cited above, other complications of severe falciparum malaria i n adults include: seizures, acute renal failure, metabolic acidosis, ARDS, haemoglob- inuri a and bleeding. In adults, jaundice, pulmonary oedema, acute renal failure, and bleeding or clotting abnormalities are more common. In children seizures, other neurological sequelae, hypoglycaemia, cough and acidosis with respira- tory distress are more frequent. While a p arasite density >5% and the presence of schizonts in a peripheral blood smear are associate d with severe disease, semi-immune individuals in highly endemic areas may have parasite de nsi- ties of 20 \200\22330% in the absence of clinical symptoms, so clear correlation betwe en counts and outcome is dif \201 cult to make. At any level of parasitaemia, the prognosi s is worse in those with higher proportions of mature parasites (mature trophozoites or sch izonts containing pigment). Treatment The parasite (and schizont) count should be monitored at least twice a day initia lly. Patients with severe malaria as well as those unable to tolerate oral therapy should b e given parenteral treatment with either a quinine-based or an artesiminin-based regimen. Q 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.