See also: Bacteriology, p224; Virology, serology, and assays, p226; Acute chest infection ( 1), p356; Acute chest infection (2), p358; Systemic in \202 ammation/multi-organ failure \200\224causes, p556; Pyrexia \200\224causes, p602; Pyrexia \200\224management, p604. 554 CHAPTER 31 Infection and in \202 ammation Infection \200\224treatment Principles \200 Drain pus. \200 Change cannula sites, if ne cessary. \200 Appropriate antibiotic therapy after laboratory specimens taken \200\224may not be necessary for mild infections where cause has been removed, e.g. an infected cathet er. Radiological and/or surgical intervention, if indicated. Antimicrobials Regular input from microbiology 9 infectious disease specialists is rec- omm ended to advise on best options for empirical therapy and for pos- sible modi \201 cation based on early communication of laboratory results (including antibiotic sensitivity patter ns). Empirical antimicrobial therapy is guided on illness severity, the likely site of infection and infecting organism(s), whether the infection is com- munity-acquired or nosocomial (in cluding Critical Care acquired), immu- nosuppression status, and known antibiotic resistanc e patterns of hospital and local community organisms. In general, critically ill patients should receive parenteral antibiotics at appropriate do sage, taking into account any impaired hepatic or renal clearance or concurrent renal repla cement therapy. Broad-spectrum therapy may be initially needed, with re \201 nement, cessa tion, or change after 2 \200\2233 days, depending on clinical response and sensitivity patt erns of organisms subsequently isolated. The duration of treatment remains highly contentio us. Apart from speci \201 c conditions such as endocarditis, tuber- culosis, and meningiti s where prolonged therapy is probably advisable, it may be suf \201 cient to stop within 3 \200\2235 days provided the patient has shown adequate signs of recovery. Patients not responding or deteriorating should be considered as either treatment failures or inappropriately treated (i.e. no infection was present in the \201 rst place). Commonl y accepted markers of infection are not speci \201 c in the critically ill patient. Indeed , pyrexia may settle on stopping antibiotic treatment. Cessation or change of antibiotic th erapy must be considered on individual merits according to the patient \200\231s condition and any subsequent laboratory results. An advantage of ceasing therapy is the ability to ta ke further specimens for culture in an antibiotic-free environ- ment. Other measures It may be necessary to remove indwelling pacemakers, tunneled vascular cathe ters, prosthetic joints, plates, implants, grafts, and stents if these are the suspected ca use of infection. This should be done in consultation with microbiologists and the appropri ate specialist as individual risk and bene \201 t need to be carefully weighed up. INFECTION \200\224TREATMENT 555 Specimen antibiotic regimens (organism unknown) 2nd/3rd generation cephalosporin OR quinolone OR carbapenem OR piptazobactam 9 Aminoglycosi de (if Gram-negative suspected) 9 Metronidazole (anaerobic cover) 9 Glycopeptide or linezol id (if MRSA suspected) 2nd/3rd generation cephalosporin + macrolide Sepsis of unknown origin Pneumonia \200\224 community-acquired 3rd generation cephalosporin OR quinolone OR carbapenem OR piptazobactam 9 aminoglycoside ( if Gram-negative suspected) + Teicoplanin, vancomycin + rifampicin or linezolid (if MRSA li kely) Pneumonia \200\224 nosocomial Skin and soft tissue Flucloxacillin (if MSSA likely) Glycopeptide or linezolid (if MRSA likely) Benzylpenicillin or clindamycin (if Streptococcus suspected) 2nd/3rd generation cephalosporin OR quinolone OR carbapenem OR piptazobactam 9 Aminoglycoside 9 metronidazole 2nd/3rd generation cephalos porin OR quinolone OR carbapenem OR piptazobactam 9 Aminoglycoside + Metronidazole 2nd/3rd generation cephalosporin OR quinolone OR carbapenem OR piptazobactam 9 Aminoglycoside Abdominal Gynecological Nephro-urological NB. Local resistance patterns should be borne in mind when prescribing. See also: Antimicrobials, p326; Acute chest infection (1), p356; Abdominal sepsis, p422; Me ningitis, p446; Tetanus, p462; Botulism, p464; Sepsis and septic shock \200\224treatment, p 560; Multi-resistant infections, p562; HIV-related disease, p566; Malaria, p568; SARS, VHF, and H5N1, p570. 556 CHAPTER 31 Infection and in \202 ammation Systemic in \202 ammation/multi-organ failure \200\224causes Exposure to an exogenous insu lt can result in an exaggerated, generalized, and often inappropriate systemic in \202 amm atory response syndrome ( \200\230SIRS \200\231). Stimulation of in \202 ammatory pathways leads to activation of macrophages, endothelium, neutrophils, platelets, coagulation, \201 brinolytic and contact systems with release of in \202 ammatory mediators and effecto rs (e.g. cyto- kines, prostanoids, proteases, free oxygen radicals, nitric oxide, endotheli n). This results in microvascular abnormalities, blood \202 ow redistribution, endo- thel ial swelling, loss of tight junctions between cells, interstitial oedema and \201 brosis, and mitochondrial dysfunction. The consequences of this may be organ dysfunction, varying from \200\230mild \200\231 to severe, and affecting single or mul- tiple organs. This may result in combinations of cardiovascular collapse, gas- trointestinal failure, renal failur e, hepatic failure, encephalopathy, neuropathy, myopathy, and/or disseminated intravascular coagulation. Acute respiratory distress syndrome (ARDS) and its milder variant acute lung injury (ALI) are the respiratory components of this pathophysiological response. Causes include: \200 \200 \200 \200 \200 \200 Infection. Trauma, burns. Pancreatitis. Inhalation injuries. Massive blood loss/transfusion . Miscellaneous including drug-related (including overdose), myocardial infarction, drownin g, hyperthermia, pulmonary embolus. De \201 nitions Systemic in \202 ammatory response syndrome (SIRS) Two or more of: \200 \200 \200 \200 Temperature >38*C or <36*C. Heart rate >90bpm. Respiratory rate >20 breaths/min or PaCO2 <3 2mmHg (4.3kPa). WBC >12,000cells/mm3, <4000/mm3, or >10% immature forms. Sepsis The systemic response to infection. De \201 nition as for SIRS but as a result of i nfection. Severe sepsis Sepsis associated with organ dysfunction or hypoperfusion. These may include, but are not limited to, lactic acidosis, oliguria, or an acute altera- tion in mental stat us. Septic shock Sepsis with hypotension, despite adequate \202 uid resuscitation, plus pres- ence of perfusion abnormalities. Multi-organ dysfunction syndrome (MODS) Presence of altered organ function in an acutely il l patient such that homeostasis cannot be maintained without intervention. Multiple organ f ailure (MOF) has not achieved worldwide uniformity of de \201 nition. SYSTEMIC INFLAMMATION/MULTI-ORGAN FAILURE \200\224CAUSES 557 See also: Acute respiratory distress syndrome (1), p360; Acute renal failure \200\224diagno sis, p400; Abdominal sepsis, p422; Pancreatitis, p424; Infection \200\224diagnosis, p552; P yrexia \200\224causes, p602. 558 CHAPTER 31 Infection and in \202 ammation Systemic in \202 ammation/multi-organ failure \200\224management Treatment is largely supp ortive though the cause should be removed/ treated, if at all possible. Treatment includes antibiotics, drainage of pus, \201 xation of femoral/pelvic fractures, and debridement of necrotic tissue. An important facet of organ support is to minimize iatrogenic trauma. It is suf \201 cient to maintain survival with relative homeostasis until recovery takes plac e rather than attempting to achieve normal physiological or bio- chemical target values. An example of this is permissive hypercapnia. International guidelines for sepsis management are produced and updated regularly. A \200 \230bundle \200\231 approach is also advocated for early and late aspects of management. Co nsensus is far from complete due to a lack of de \201 nitive outcome studies or prospectiv e validation of the recommenda- tions. However, opinion is unanimous on the need for early recognition and intervention of sepsis. Local policies may favor eclectic therapies based o n small trials/case series/anecdotal success or a reasonable theoretical basis for administ ration. Examples include antioxidants, protease inhibitors, immunonutrition, plasmapheresis , vasodilators, and immunoglobulin. It is generally agreed that rapid resuscitation and res toration of oxygen delivery, glycaemic control, and prompt removal of any treatable cause i s desirable in preventing the onset of SIRS or progression of organ failure. Because of non-standardization of de \201 nitions, outcome data are con- \202 icting; si ngle organ \200\230failure \200\231 carries 20 \200\22330% mortality while \211 3 organ \200\230failures \200\231 lasting \211 3 days carries >40 \200\22350% mortality. Recovery is often complete in survivors, though recent studies reveal long-term physical and psychol ogical sequelae in a signi \201 cant proportion. Principles of management The following represent the authors \200\231 current practice. Respiratory SaO2 >90 \200\22395% (may have to settle for lower) Permissive hypercapnia Cardiovascular Maintain cardiac output/oxygen delivery and blood pressure compatible with adequate organ p erfusion (e.g. no metabolic acidosis) Renal Maintain adequate metabolic and \202 uid homeostasis by intravascular \201 lling, diure tics, vasoactive agents, and/or haemo(dia) \201 ltration Maintain hemoglobin >7g/dL, plate lets >20 \200\22340 x 109/L, INR <1.5 \200\2232.5 Hematological Gastrointestinal Stress ulcer prophylaxis (consider stopping once enteral nutrition is established) Infection Antibiotics, pus drainage, good infection control Nutrition Preferably started early and by enteral route LMW heparin 9 thromboembolic stockings Freque nt turns, low pressure support surfaces, nursing care, and physiotherapy DVT prophylaxis Pressure area/mouth/ joint care Psychological Support to both patient and family SYSTEMIC INFLAMMATION/MULTI-ORGAN FAILURE \200\224MANAGEMENT 559 Key paper Dellinger RP Levy MD, Carlet JM, et al. (2008) Surviving Sepsis Campaign: Interna tional guidelines for management of severe sepsis and septic shock. Crit Care Med 36: 296 \200\223327. See aslo: Ventilatory support \200\224indications, p44; Enteral nutrition, p128; Tight glyc aemic control/intensive insulin therapy, p132; Acute respiratory distress syndrome (2), p36 2; Hypotension, p380; Acute renal failure \200\224management, p402; Infection \200\224treat ment, p554; Sepsis and septic shock \200\224 treatment, p560; Pyrexia \200\224management, p 604. 560 CHAPTER 31 Infection and in \202 ammation Sepsis and septic shock \200\224treatment Principles of treatment As for other causes of mu lti-organ dysfunction syndrome, outcome in sepsis improves with: 1. Prompt diagnosis and tr eatment of the underlying cause. 2. Rapid resuscitation to prevent prolonged tissue hypoxia . 3. Good glycaemic control. 4. Strict infection control. 5. Recognition and appropriate tr eatment of secondary infections. 6. Adequate nutrition. 7. Recognition that \200\230normal \200\231 physiological/biochemical levels do not nec- essarily need to be attained while t he patient is critically ill, provided he/she is not compromised. For example, a mean BP of 55 \200\22360mmHg is often acceptable unless evidence of poor perfusion or ischaemia sugge sts higher levels should be sought. 8. Avoidance of preventable mishaps, e.g. prolonged hypotension, pres- sure sores, thromboembolism. 9. Temperature control in the range 36 \200\22338.5*C. 10. Prevention of contractures, earl y mobilization, etc. 11. Speci \201 c treatments (see below). Speci \201 c treatments for severe sepsis/septic shock 1. Activated protein C signi \201 cantly improved outcome in patients with \211 2 organ dysfunctions if commenced <48h of on set. Issues about safety and ef \201 cacy, particularly in less severely septic patients, has prompted a repeat study that is currently in progress. 2. \200\230Low-dose \200\231 hydrocortisone (50mg 6-hourly) + \202 udrocortisone (50mcg daily) given for 7 days improved survival in \200\230pressor-unresponsive \200\231 shock if commenced <8h of presentation, though only in the subset with an abnormal cortisol respons e to synthetic ACTH. The recent CORTICUS trial (5 days \200\231 hydrocortisone 50mg 6-hourl y, reducing over the next 6 days in all patients with septic shock <48h) failed to con \201 rm the utility of Synacthen testing and the overall bene \201 t of steroid use. 3. Th e VASST study found \200\230low-dose \200\231 vasopressin (0.01 \200\2230.03U/min) produce d survival bene \201 t over norepinephrine in less severe shock (de \201 ned as requiring <15mcg/min norepinephrine) and equivalent out- comes in more severe cases. 4. No overall difference was shown between epinephrine and norepine- phrine (9 dobutamine). Our current practice is based on the pharma- cological rationale of epinephrine (inotrope + pressor) for low output shock and norepinephrine (pressor) for high output shock. 5. For pressor-resistant septic shock, i.e. high-output severe hypotension not responding t o adequate \202 uid loading, norepinephrine >0.4mcg/kg/ min, and hydrocortisone, we consi der use of terlipressin (or methylth- ioninium chloride (methylene blue)). Until more data are upcoming, these agents should be viewed as rescue therapies rather than a straight alte rnative for norepinephrine. 6. For continuing resistant shock, we consider plasmapheresis, glucose- insulin-potassium i nfusion (for low output shock) or high output haemo \201 ltration. The evidence base for t hese therapies is weak. SEPSIS AND SEPTIC SHOCK \200\224TREATMENT 561 Sepsis resuscitation bundle More details are available at <http://ssc.sccm.org> Complete wi thin 6h: 1. Measure serum lactate. 2. Obtain blood cultures prior to antibiotic administrat ion. 3. Administer broad-spectrum antibiotic within 3h of Emergency depart- ment admission and within 1h of non-emergency department admis- sion. 4. In the event of hypotension and/or serum lactate >4mmol/L: (i) deliver initial minimum o f 20mL/kg of crystalloid or an equivalent volume of colloid, and (ii) give vasopressors to keep mean BP >65mmHg if not responding to \202 uid. 5. If still hypotensive despite \202 uid resuscitation and/or lactate >4mmol/L, achieve CVP >8mm Hg and ScvO2 >70% or SvO2 >65%. Complete within 24h: 1. Give low-dose steroids for shock according to local policy. 2. Admi nister activated protein C according to local policy. 3. Maintain glucose control between 7 0 \200\223150mg/dL (3.9 \200\2238.3mmol/L). 4. Maintain median inspiratory plateau pressure <30cmH2O. Key papers Bernard GR, Vincent JL, Laterre PF, et al. for the PROWESS study group. (2001) E f \201 cacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699 \200\223709. Annane D, S bille V, Charpentier C, et al. (2002) Effect of treatment with low doses of hy drocorti- sone and \202 udrocortisone on mortality in patients with septic shock. JAMA 28 8: 862 \200\22371. Annane D, Vignon P, Renault A, et al. for the CATS Study Group. (2007) Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial. Lan cet 370: 676 \200\22384. Sprung CL, Annnane D, Keh D, et al. for the Corticus Study Group. (2008). Hydrocortisone th erapy for patients with septic shock. N Engl J Med 358: 111 \200\22324. Russell JA, Walley KR, Singer J, et al. for VASST Investigators. (2008) Vasopressin vs nore pinephrine infusion in patients with septic shock. N Engl J Med 358: 877 \200\22387. Dellinger RP Levy MD, Carlet JM, et al. (2008) Surviving Sepsis Campaign: International gui delines for management of severe sepsis and septic shock. Crit Care Med 36: 296 \200\223327 . See also: Ventilatory support \200\224indications, p44; Enteral nutrition, p128; Tight glyc aemic control/intensive insulin therapy, p132; Bacteriology, p224; Virology, serology, and assays, p226; Lactate, p236; Inotropes, p264; Vasopressors, p268; Antimicrobials, p326; Cor ticosteroids, p328; Immunomodulatory thera- pies in sepsis, p332; Basic resuscitation, p338 ; Abdominal sepsis, p422; Infection \200\224diagnosis, p552; Infection \200\224treatment, p 554; Systemic in \202 ammation/multi-organ failure \200\224causes, p556; Pyrexia \200\224 causes, p602; Pyrexia \200\224management, p604. 562 CHAPTER 31 Infection and in \202 ammation Multi-resistant infections Background to multi-resistance A major problem worldwide is the increasing incidence of infections caused by multi-resistant organisms. These include: \200 Gram-positive organisms, notably methicillin-resistant S. aureus (MRSA) and vancomycin-resi stant Enterococcus (VRE). Gram-negative bacteria, e.g. multi-resistant Acinetobacter and Ps eudomonas, carbapenem-resistant Klebsiella pneumoniae. Fungi, e.g. non-albicans Candida spe cies that are increasingly \202 uconazole-resistant. Atypical organisms, including multi- resistant M. tuberculosis, malaria, Pneumocystis jiroveci (previously Pneumocystis carinii) . The predominant factor underlying this worrying rise is the widespread and often inappropri ate use of antibiotics. Prevention Prevention is key so concerted and maintained efforts must be made to minimize a ntibiotic use: \200 \200 Is sepsis/infection a likely diagnosis? If not, do not give antibiotics. Is antibiotic prop hylaxis needed? Increasingly, surgery can be performed without the need for prophylaxis or with only 1 \200\2233 doses. Prolonged courses should be avoided. If antibiotics are prescr ibed for presumed infection/sepsis, consider the need for their continuation daily. Sadly, optimal duration for a course of antibiotics remains poorly de \201 ned. Antibiotics shoul d be stopped promptly if the diagnosis turns out to be non-infective; there is no point in \201 nishing a full course. For infection, antibiotics should be stopped 1 \200\2232 days after resolution of clinical symptoms. UK practice tends towards 3 \200\2237 day courses f or \200\230uncomplicated \200\231 infections (e.g. without bone or heart valve involvement ). Course duration tends to be longer in mainland Europe and North America. If an organism is isolated and sensitivities known, consider changing from broad-spectrum combinations to targeted monotherapy Management When prescribing antibiotics consider the likelihood of multi-resistance in the following patients: \200 \200 \200 Inpatient for \211 3 days. Recently hospitalized. Recently in an area with known high resi stance rates, e.g. penicillin- resistant meningococcus from Spain. Patients colonized/infected with multi-resistant organisms should, in general, be placed in source isolation to protect other patients. However, strong evidence for ef \201 cacy is lacking. Source isolation is probably more relevant for airborne (aerosolised) organisms sp read by coughing and organisms producing diarrhoeal illnesses. Strict hand hygiene, glove a nd gown wearing, and other local infection control policies should be observed. Decolonisation regimens may be considered for MRSA, e.g. chlorhexi- dine bodywashes and top ical antibiotics (e.g. mupirocin) nasally and/or orally. Again, the evidence base for ef \201 cacy is not very strong. MULTI-RESISTANT INFECTIONS 563 See also: Bacteriology, p224; Virology, serology, and assays, p226; Antimicrobials, p326; I nfection control \200\224 general principles, p544; Infection control \200\224dangerous pat hogens, p546. 564 CHAPTER 31 Infection and in \202 ammation Necrotising fasciitis This is a rapidly spreading and often lethal soft tissue infection ca used pre- dominantly by group A B-haemolytic Streptococci, but also by other Gram- positive bacteria, e.g. Panton \200\223Valentine Leukocidin S. aureus, Clostridium species (e.g C. novyi in skin poppers), Enterococci, and Gram-negative bacteria such as E. Coli and Klebsie lla. Two thirds are polymicrobial. It can involve any layer within the soft tissue compartm ent (dermis, subcu- taneous tissue, super \201 cial or deep fascia, muscle) and is associa ted with tissue necrosis. Though not usually associated with abscess formation, it can orig inate from untreated/inadequately drained abscesses. Risk factors \200 \200 \200 Intramuscular/subcutaneous drug injection (especially illicit). Chronic comorbidities, e.g. diabetes, immunosuppression, obesity. Recent surgery. Diagnosis \200 \200 \200 Can be dif \201 cult initially so have a high index of suspicion. Swelling, erythema, pain over affected area. As infection progresses, tense oedema (appears around the area of comp romised skin), degree of pain disproportionate to clinical appearance, skin discoloration, subcutaneous bruising, blisters/bullae, necrosis, crepitus, and/or subcutaneous gas. Fever, tachycardia, hypotension, shock. Elevated creatine kinase, markers of in \202 ammation (C RP, procalcitonin), hyponatraemia, hyperglycaemia, neutrophilia. CT/MRI (shows subcutaenous gas and in \202 amed fascia) or X-ray (identi \201 es subcutaneous gas) have high sensit ivity but low speci \201 city. \200 Treatment \200 Source control \200\224urgent and complete debridement is crucial by an experienced surgeon (ideally, a plastic surgeon) to ensure adequate debridement has been performed. After surg ery, the patient \200\231s condition is often considerably worse. Frequent repeat debrideme nts are needed until it is clear the fasciitis is not spreading. Antibiotics \200\224this i s an important adjunct to source control. High- dose clindamycin, a potent protein synthesi s inhibitor, inhibits toxin production, particularly in Streptococcus and Clostridium infec tion. This is given in combination with high-dose benzylpenicillin (or a carbapenem if peni cillin allergic) 9 an aminoglycoside (if Gram-negative infection suspected) 9 a glycopeptid e or linezolid (if MRSA suspected). Continue until no further debridements are needed. Crit ical care support \200\224such patients are often very sick requiring multiple organ suppor t, correction of coagulopathy, blood transfusion to replace blood loss from the debrided ar ea, and consideration of activated protein C. Intravenous immunoglobulin (IV Ig) has been u sed successfully in small randomized studies, particularly for toxin-related infection due to group A Streptococcus or Clostridium. Current UK recommendations support its use in pati ents who do not respond to standard measures. Hyperbaric oxygen has been advocated in some small series, but this should not delay or prevent surgical debridement. NECROTISING FASCIITIS 565 See also: Bacteriology, p224; Antimicrobials, p326; Immunomodulatory therapies in sepsis, p 332; Infection \200\224 diagnosis, p552; Infection \200\224treatment, p554; Sepsis and sept ic shock \200\224treatment, p560. 566 CHAPTER 31 Infection and in \202 ammation HIV-related disease Patients with HIV-related diseases may present to critical care electiv ely after surgical procedures, including diagnostic biopsies of brain or lung. Other cases present with complications of HIV-related disease, espe- cially pulmonary infection (e.g. P neumocystis jiroveci, CMV, TB) or seizures (e.g. cerebral lymphoma, cerebral abscess, menin gitis). HIV-related disease is now considered to be a chronic manageable condition with a g ood short-term prognosis. It is reasonable to offer critical care support. As a group, IV drug abusers are at high risk for HIV-related disease. However, they tend to present to critical care more commonly as a result of the drug abuse (e.g. drug withdrawal syndromes, overdose, sepsis, endocarditis, hepatitis, rhabdomyolysis). An HIV specialist should be consulted about continuing or commencing antiretroviral drugs i n patients with known or newly diagnosed HIV infec- tion. Risks of resistance, dif \201 cu lties in administration of oral medications, possible contraindicated use of proton pump in hibitors and H2 blockers, delayed renal and/or hepatic clearance, drug interactions and tox icity (e.g. acute hypersensitivity reactions, immune reconstitution syndrome (IRS), Stevens \200\223Johnson syndrome, pancreatitis, lactic acidosis) should all be con- sidered. Recen t evidence suggests antiretrovirals are not responsible for improved critical care outcomes . Pneumocystis jiroveci (carinii) pneumonia \200 The commonest respiratory disorder affecting HIV patients. Prognosis has improved considera bly in recent years, even in those requiring mechanical ventilation. Intensive, early suppo rt with CPAP and appropriate chemotherapy may avert the need for ventilatory support. Diagn osis is made clinically without waiting for laboratory con \201 rmation. First-line drug t reatment is with high dose co-trimoxazole or pentamidine plus adjuvant high dose steroids. The onset of effect of co-trimoxazole is quicker and it has a broader spectrum of antibacte rial activity covering common secondary pathogens. Pentamidine is usually used where co-tri moxazole fails or cannot be taken (e.g. allergy). Methylprednisolone is used to suppress pe ribronchial \201 brosis and alveolar in \201 ltrate. There may be an initial deteriorati on on treatment. Respiratory support is provided initially with CPAP (5 \200\22310cmH2O) if hypoxaemic despite high FIO2 (or BiPAP if the patient is tiring). Lower CPAP pressures sho uld be used where possible since such patients carry a considerable risk of developing pneu mothorax. Mechanical ventilation is reserved for those who have a rising respiratory rate w ith deteriorating gas exchange and fatigue despite NIV. Chest X-ray changes respond very sl owly. Avoid excessive \202 uid as considerable capillary leak can occur. \200 \200 Immune reconstitution syndrome (IRS) Occurs days to weeks after initiation of antiretrovira l therapy. Characterized by paradoxical worsening of symptoms. It results from an exaggerat ed in \202 ammatory response to Pneumocystis, Mycobacterial, viral, or other antigens. It can lead to fever, lymphadenpathy, respiratory failure, hepatitis, CNS, and skin manifestat ions. Diagnosis is by exclusion of other causes. Management includes treatment of infection and corticosteroids. Continue antiretroviral therapy unless life-threatening. HIV-RELATED DISEASE 567 Drug Dosages Co-trimoxazole 120mg/kg/d in divided doses IV for 10 \200\22314 days, then PO to complete 21 days Pentamidine 4mg/kg/d IV Methylprednisolone 1g/d for 3 days Key paper Huang L, Quartin A, Jones D, et al. (2006) Intensive care of patients with HIV in fection. N Engl J Med 355: 173 \200\22381. See also: Ventilatory support \200\224indications, p44; Continuous positive airway pressure , p70; Non-invasive respiratory support, p76; Antimicrobials, p326; Corticosteroids, p328; Infection control \200\224general principles, p544; Infection control \200\224HIV, p546. 568 CHAPTER 31 Infection and in \202 ammation Malaria Malaria should be suspected in any patient returning from endemic areas with a febr ile illness which may have cerebral, abdominal, lung, or renal features. Rarely, people liv ing near airports may be bitten by a transported Anopheles mosquito. There may be considera ble delay (weeks to months) between the mosquito bite and signs of infection. It is caused by protozoal infection with the Plasmodium genus. The most severe form is P. falciparum whi ch causes malignant, tertian malaria. Other forms (P. malariae, P. vivax, P. ovale) rarely cause life-threatening disease. Pathophysiology P. falciparum invades erythrocytes regardless of age. High levels of para- sitaemia >5% are considered severe in non-immune travelers. The cells may haemolyse or be d estroyed in liver or spleen. Anemia may be severe. Increased vascular permeability, cytokin e release, red cell agglutination, and intravascular coagulation (DIC) may also occur. Clinical features \200 Symptoms include headache, fever with rigors, myalgia, abdominal pain, vomiting, and diarrh ea. Signs include splenomegaly, jaundice, tender hepatomegaly, and anemia. Hyponatraemia is common. A minority have paroxysms of fever with \200\230cold \200\231 and \200\230hot \200\231 stages. If >5% parasitaemia, features include: \200 \200 \200 Cerebral malaria, causing coma, delirium, seizures, or focal de \201 cits. Cough and haemo ptysis or acute respiratory distress. Blackwater fever is associated with massive intravasc ular haemolysis, jaundice, haemoglobinuria, collapse, and renal failure. Acute renal dysfun ction occurs in a third of adult ICU patients. Acute cardiovascular collapse ( \200\230algi d malaria \200\231) and metabolic acidosis. Thrombocytopaenia, DIC, and spontaneous bleedin g. \200 \200 Diagnosis \200 Plasmodia are seen in RBC in thick or thin smears of peripheral blood. Parasitaemia intensi ty may vary from hour to hour and may be scanty. Carefully scrutinize the smear and repeat if doubt persists. Leucocytosis is not a feature of malaria. Splenomegaly is almost invaria ble during the second week of illness. \200 Treatment 1. Early IV quinine infusion is the mainstay of treatment of severe malaria. Comp lications include hypoglycaemia and tinnitus. Artemether should be considered in cases of l ikely quinine resistance, or as \201 rst-line treat- ment for uncomplicated cases. 2. Consider a 2 \200\2233L exchange transfusion if the patient is severely ill and parasitaemia levels >10 \200\22320%. 3. Pay careful attention to \202 uid and electrolyte balance. Excess \202 uid should be avoided as these patients have increased capillary leak. 4. Treatment of hypoglyc aemia, renal failure, coagulopathy, metabolic aci- dosis, seizures, etc. follow conventional lines. 5. Steroids are not recommended for cerebral oedema. 6. Malaria patients are immunosuppress ed and prone to atypical infection. Suspect Gram-negative infection with circulatory collapse. MALARIA 569 Drug dosages First-line Quinine 20mg quinine salt/kg IV over 4h, then 10mg/kg infusion over 4h, repeated 8-hourly until the patient can swallow, then tablets (10mg quinine salt/kg 8-hourly) to complete a 7-day cour se. Halve maintenance dose to 5mg salt/kg 8-hourly if continuing parenteral therapy for >48 h. Artemether 3.2mg/kg IM followed by 1.6mg/kg daily Second-line after asexual parasites eliminated Sulfadoxine 500mg / pyramethamine 25mg 3 tablets once Doxycycline 200mg, then 100mg daily for 7 days See also: Acute respiratory distress syndrome (1), p360; Acute respiratory distress syndrom e (2), p362; Oliguria, p398; Acute renal failure \200\224diagnosis, p400; Acute renal failu re \200\224management, p402; Jaundice, p428; Coma, p438; Generalized seizures, p444; Anemia , p472; Haemolysis, p476; Pyrexia \200\224causes, p602; Pyrexia \200\224management, p604. CHAPTER 31 Infection and In \202 ammation 570 SARS, VHF, and H5N1 SARS SARS is a severe respiratory disease caused by a coronavirus. It w as \201 rst recognized in China in November 2002 and spread worldwide before being contai ned by July 2003. Further outbreaks were recognized over the following year. The possibilit y of SARS re-emergence remains. Treatment is supportive with source isolation. Various trea tments, including ribavirin, corticosteroids, interferon, and intravenous immunoglobulin, h ave not shown con \201 rmed outcome bene \201 t. Viral haemorrhagic fever (VHF) VHF is a group of viral infections that cause a severe haemo rrhagic disease. They include Lassa, Ebola, and Marburg fevers. Treatment is supportive and mortality high for these highly contagious pathogens. In some countries, such patients are managed in a high-risk Infectious Diseases Unit with per- sonal protective equipment for s taff. These units generally have restricted access, lobbied entrance to isolation rooms, ne gative pressure with HEPA \201 ltration for exhaust air, en suite facilities, and staff s hower and change facilities. Protective suits limit the time staff can work to four hours. In other countries, these patients are managed in bed isolator tents (Trexler units) with t he provision of all care via invaginated sleeves into the tent. The provision of intensive care within a Trexler tent is nearly impossible. H5N1 H5N1 is an avian in \202 uenza A virus that has caused illness in humans. There is ev idence of limited human-to-human transmission and transmission of the virus to those handli ng of infected poultry. Around 60% of humans known to have been infected with the recent As ian strain have died. H5N1 may mutate into a strain capable of ef \201 cient human-to-huma n transmis- sion. Treatment is supportive although oseltamivir may inhibit the virus from s preading within the body. SARS, VHF, AND H5N1 571 See also: Infection control \200\224general principles, p544; Infection control \200\224dan gerous pathogens, p548. 572 CHAPTER 31 Infection and in \202 ammation Rheumatic disorders Rheumatoid arthritis A debilitating arthritis that may present to criti cal care through pulmo- nary involvement or through complications of treatment (e.g. renal failure, immunosuppression, bleeding disorders). Pleuro-pulmonary involvement may precede a rthritic symptoms and is more common in those with active rheumatoid disease and middle-age d men. Care is required when intu- bating patients with rheumatoid arthritis since the neck joints may sublux. Advice should be sought from a rheumatologist about starting/continuing treatment with steroids or other disease modi \201 ers such as methotrexate, anti-TNF ant ibody, or rituximab. Rheumatoid pleurisy Often presents with effusion and can be asymptomatic. Effusions may be recurrent or chronic and may impede respiratory function. The effusion is an exudate, low i n glucose, and often high in cholesterol. Rheumatoid lung A diffuse interstitial pneumonitis with bibasal \201 brotic changes on ch est X-ray or CT. It produces a restrictive pulmonary defect. The mainstay of treatment is e arly systemic corticosteroid therapy. Systemic lupus erythematosis (SLE) A non-organ speci \201 c autoimmune disease characteriz ed by anti-nuclear antibodies with high titres of anti-double stranded DNA antibodies. Vasc ulitis is prominent though cutaneous and CNS involvement are not vasculitic. SLE may presen t to intensive care through pulmonary, renal, or central nervous system involvement. Renal failure Renal failure is vasculitic in origin and may progress to end-stage renal fai lure requiring long-term dialysis. Early treatment with systemic steroids and immunosuppres sives may halt the disease progress. Lupus pleurisy and pericarditis Unlike rheumatoid pleurisy, pleural involvement in SLE is o ften painful and associated with large pleural effusions. Pulmonary hemorrhage This is associated with renal failure and may be life-threatening. Pla sma exchange may be helpful. Interstitial pneumonitis Interstitial pneumonitis is uncommon. Parenchymal in \201 ltrates are more likely to be infective in origin, secondary to immunosuppressive therapy. Pulmonary thromboembolic disease Patients typically have a prolonged APTT due to circulatin g lupus antico- agulant but are more prone to thrombotic episodes. Lupus anticoagulant is a ssociated with anticardiolipin antibodies. Recurrent pulmonary emboli may be associated wit h chronic pulmonary hypertension. Treatment is long-term anticoagulation. RHEUMATIC DISORDERS 573 See also: Respiratory imaging, p158; Anticoagulants, p318; Corticosteroids, p328; Rituximab , p334; Pulmonary embolus, p376; Acute renal failure \200\224diagnosis, p400; Acute renal f ailure \200\224management, p402; Vasculitis, p574. 574 CHAPTER 31 Infection and in \202 ammation Vasculitis Vasculitis should be suspected in any patient with multisystem disease, especial ly involving the lungs and kidneys. Wegener \200\231s granulomatosis A systemic vasculitis characterized by necrotising granulo mas of the upper and lower respiratory tract, glomerulonephritis, and small vessel vasculit is. Wegener \200\231s granulomatosis is associated with positive core anti-neutrophil cytop lasmic antibodies (c-ANCA), particularly granular with central attenuation on immuno \202 uorescence. Intensive care admission is usually because of renal and pulmonary involvement. Renal failure Focal necrotising glomerulonephritis leads to progressive failure. Treatment with steroids and cyclophosphamide may give complete remission. Upper airway disease Nasal symptoms include epistaxis, nasal discharge, and septal perforat ion. Critical care admission may be required for severe epistaxis. Ulcerating lesions of th e larynx and trachea may cause subglottic stenosis. This is usually insidious but may prese nt problems on attempted intubation. Pulmonary involvement Usually associated with haemoptysis, dyspnoea, and cough with rounded opacities 9 cavitation on chest X-ray/CT. Nodules may be solitary. Alveolar hemorrhage may be life-threatening. The mainstay of treatment is steroids and cyclophosphamide which may produce complete remis- sion. Plasma exchange may be helpful. Polyarteritis nodosa (PAN) PAN is a necrotising vasculitis affecting small and medium-sized mus- cular arteries. Intensive care admission may be provoked by renal failure, ischaemic heart disease, hypertensive crisis, and bronchospasm although true pulmonary involvement is uncommon. Diagnosis may be con \201 rmed by mesenteric angiography or renal biopsy. Treat ment involves renal replacement therapy, high dose steroids, and cyclophosphamide. Goodpasture \200\231s syndrome Anti-glomerular basement membrane (anti-GBM) antibodies bind at the glomerulus and alveolus. Patients present with a proliferative glomeru- lonephritis and haemoptysis. Diagnosis is con \201 rmed by positive anti-GBM antibodies and renal bio psy. Treatment is with immunosuppressive therapy and plasma exchange. VASCULITIS 575 See also: Plasma exchange, p114; Corticosteroids, p328; Airway obstruction, p348; Haemoptys is, p372; Acute renal failure \200\224diagnosis, p400; Acute renal failure \200\224manageme nt, p402; Rheumatic disorders, p572. 576 CHAPTER 31 Infection and in \202 ammation Toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is an acute onset, potentially life-threatening, idiosyncratic mucocutaneous reaction, usually occurring after starting a new drug, e.g. antibiotics, non-steroidal anti-in \202 ammatory drugs, anticon- vulsants, allopurinol or, less commonly, immunization. It is often compli- cated by infection and mul ti-organ dysfunction. Mortality is 25 \200\22375%, often from secondary sepsis. Clinical features \200 \200 There is often a \202 u-like prodrome for 2 \200\2233 days. Macular rash that may become con \202 uent, with desquamation of skin and mucosae leaving raw, moist, denuded surfaces. Conjunctivitis may precede skin changes by 1 \200\2233 days. More common in women patients with HIV disease. Relevant drugs will have been started within the previous four weeks. \200 \200 Management \200 