Mark Nelson, Rachel Jones, and James Millard
The majority of patients admitted to intensive care units (ICUs) will receive treatment for infection either as the primary cause of admission or as sequelae of being critically unwell. Defined as infection that begins >48 h after hospital admission, nosocomial infections or healthcare-associated infections (HCAIs) are associated with increased mortality, morbidity, and length of stay. The risk of infection is increased with increased duration of stay on the ICU and the severity of illness. Rates of nosocomial infection on the ICU are up to five times higher than those on the general ward population.
Reasons for this include:
• More acute and severe physiological derangements.
• Greater incidence of ill-health and existence of chronic comorbidities among patients admitted to the ICU.
• Immunosuppression—illness-induced or therapeutic.
• The use of multiple indwelling devices such as urinary catheters and central venous catheters (CVCs) is extremely common.
• High levels of activity means the increased number of patient–healthcare professional contacts.
• High prevalence of resistant organisms and widespread use of broad-spectrum antibiotics.
Common ICU HCAIs include:
• Ventilator-associated pneumonia (VAP).
• Urinary catheter-related infection.
• Catheter-related bloodstream infections (CRBSI).
HCAIs are potentially preventable adverse events and avoidance is the joint responsibility of all healthcare professionals.
Approximately 39 per 1000 patients in English ICUs develop device-related bacteraemia, with the vast majority of these being due to CVCs. CRBSIs are most commonly caused by skin organisms that colonize the exit site and catheter hub. These may contaminate the catheter during insertion or be transferred from the hands of staff during care interventions. Microbiological confirmation can be either by quantitative culture of the catheter tip or by differences in growth between catheter and peripheral venepuncture blood culture specimens. Coagulase-negative staphylococci such as Staphylococcus epidermidis are most commonly implicated, followed by Staphylococcus aureus, Candida species, and enterococci. There is a subtle difference between the term CRBSI and central line-associated bloodstream infection (CLABSI). Confirmation of a CLABSI requires microbiological confirmation as well as a clinical/microbiological review of the patient.
A range of techniques is associated with reduced rates of CRBSI. The Matching Michigan initiative introduced a set of interventions known as care bundles, which have been shown to reduce infection rates as well as deaths from CRBSI. These interventions include:
• During insertion, scrupulous hand hygiene together with the use of maximal sterile barriers, including a sterile gown, sterile gloves, and a large sterile drape is observed. The skin should be cleansed with alcoholic chlorhexidine gluconate solution or with 5% povidone-iodine if patients are sensitive to chlorhexidine.
• Insertion of the line into a subclavian site appears to be associated with lower rates of infection than femoral or internal jugular sites, and should be used unless medically contraindicated. This may, however, be associated with an increased risk of complications.
• The number of lumens should be minimized and a dedicated lumen should be kept exclusively for lipid-containing fluid such as parenteral nutrition.
• Antimicrobial- or silver-impregnated lines are available and may be appropriate in patients requiring short-term central venous access and who are at high risk of CRBSI.
• Sterile, transparent semipermeable dressings allow visualization of the insertion site. Hand hygiene during the use of the CVC should also be meticulous.
• Central lines should not be replaced routinely but on evidence of infection. Guidewire-assisted exchange should be avoided as far as possible for line replacement.
• Daily review of line necessity and prompt removal of unnecessary lines is performed. Signs of local infection at the site of insertion should prompt consideration for line removal.
VAP is a common complication on the ICU, with an incidence rate of between 15% and 20%, and has a mortality rate of between 20% and 50%. Diagnosing VAP and hence measuring the rates is challenging as no gold standard definition exists. More recently, the Centre for Disease Control and Prevention introduced the term ventilator-associated events in response to this uncertainty. It replaces the previous definition with a hierarchy of escalating pathological and clinical conditions: ventilator-associated conditions, infection-related ventilator-associated conditions, and VAP. Scoring systems such as the Clinical Pulmonary Infection Score can also be utilized to increase diagnostic accuracy.
The pathogenesis of VAP is thought to be due to microaspirations of secretions containing pathogenic bacteria that have pooled above the cuff of the endotracheal tube. Microbiological sampling can involve invasive diagnostic methods using quantitative culture of a bronchoscopic protected specimen brush or bronchoalveolar lavage samples, which improve specificity of the diagnosis.
Like CRBSI, VAP rates can be reduced through a bundle of care approach, which generally aims to prevent or reduce aspiration. These include:
• Head-of-bed elevation 30°–45°.
• Reinforcement of hand hygiene practice.
• Sterile suction and handling of respiratory equipment.
• Change ventilator circuit if visibly soiled or mechanically malfunctioning.
• Proper timed mouthcare with normal saline and suction of oropharyngeal secretions.
• Daily evaluation for readiness of extubation and reducing the amount of sedation used.
• The use of selective digestive decontamination remains controversial (see section on ‘Selective decontamination of the digestive tract’).
Catheter-associated urinary tract infection (UTI) is the most common nosocomial infection in hospitals, 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 appears to reduce rates of catheter-associated UTI. Most importantly, local guidelines should be followed for care of urinary catheters, with early removal of the catheter if possible.
Antimicrobial stewardship and resistance
Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi. It is an increasingly serious threat to global public health that requires action across all government sectors and society.
Antimicrobial stewardship is defined as ‘an ongoing effort by a health-care institution to optimise antimicrobial use among hospital patients in order to improve patient outcomes, ensure cost-effective therapy and reduce adverse sequelae of antimicrobial use’. This includes a combination of strategies such as robust clinical guidelines, educational programmes, and appropriate audit and quality improvement tools. There is a need to reduce unnecessary use of broad-spectrum antibiotics and encourage appropriate de-escalation strategies. Appropriate collection of specimens and careful interpretation of culture results helps to differentiate between organisms that are contaminating specimens or colonizing the patient and organisms that are causing infection. Therapy should be adjusted to the narrowest effective spectrum based on culture results, and antibiotics should be stopped as soon as there is cure or if no evidence of infection is found.
Involvement of local infectious disease or microbiology clinicians improves patient outcomes and decreases treatment costs in serious infections. Based on information about the local population and susceptibility patterns of pathogens, guidelines and policies can be developed, implemented, and audited by the multidisciplinary team.
Prevention of transmission of infection
Two basic principles govern the measures that should be taken to prevent transmission of infection within the healthcare setting:
• Stop the route of transmission.
• Isolate the infection source.
Hospital environmental hygiene
The most important source of transmitted infection is the hands of health workers, but almost every item of equipment in the ICU has been shown to be a source of nosocomial infection. The environment must be kept clean, and surfaces damp-dusted at least daily. Routine use of disinfectants is not necessary, but disinfection of isolation rooms or areas where patients with multiresistant organisms have been nursed should be carried out as per local infection control recommendations.
Despite the hands being the most common vector for infection, compliance rates of ICU handwashing procedures average 30–40%. Rates can be improved with the use of hand disinfection with alcohol-based antiseptic hand rubs, which are highly effective and quick to use. Hands that are visibly soiled should be washed in soap and water. Handwashing is more effective against certain diarrhoeal pathogens such as Norovirus and the spores of Clostridium difficile. Hygienic handwashing refers to washing hands with an antiseptic agent added to the detergent, and should be used when prolonged reduction in microbial flora 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 descriptive studies and clinical trials.
Personal protective equipment
Appropriate use of aprons, gowns, gloves, protective eyewear, and facemasks protects staff and prevents transmission 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 decontaminated after each care activity for a patient. Particulate filter masks are worn when caring for patients with respiratory infections transmitted by airborne particles, such as Mycobacterium tuberculosis or epidemic influenza. Facemasks and eyewear protect mucous membranes from splashes. Facemasks have not been shown to protect patients from HCAIs during routine ward procedures. There are concerns, however, about the ‘cloud’ healthcare provider phenomenon, whereby viral upper respiratory tract infection promotes transmission of pathogens such as meticillin-resistant S. aureus (MRSA) that colonize the oropharynx. Some of this transmission may be prevented by facemasks, although healthcare workers may provide better protection to their patients by staying away from work when unwell themselves.
Two types of isolation (or barrier nursing) are used in the ICU setting: ‘protective’ or ‘source’. Immunocompromised patients need protective isolation from pathogens circulating in ICU. Patients with communicable diseases or carrying multiresistant bacteria are cared for in source isolation to protect 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 cohorting. Although not an exhaustive list, some of the organisms that should prompt isolation include MRSA, C. difficile, vancomycin-resistant Enterococcus (VRE), and multiresistant Gram-negative bacteria such as multiresistant Acinetobacter baumannii.
Patients may be colonized with multiresistant organisms but not manifest active infection and so may not be recognized. Screening for these organisms on admission to ICU is important to provide appropriate isolation or cohorting of colonized patients. Up to 86% of VRE or MRSA-colonized patients will not be recognized except by active surveillance. New rapid (hours) point-of-care techniques are becoming more readily available for screening.
Consult infection control team
The infection control team is responsible for:
• 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 define sources of cross-infection more rapidly, evaluate control methods, and informs resource allocation in infection control. There are various ways that this may be achieved, but surveillance is best conducted prospectively by staff trained in infection control.
The strict application of barrier nursing techniques in ICU may break down during periods of understaffing or overcrowding, and this has been associated with outbreaks of nosocomial infection.
The advent of highly active antiretroviral therapy (HAART) has transformed the outlook of individuals living with human immunodeficiency virus (HIV). Prior to this, in the early years of the epidemic, survival from infection was approximately 10 years and the emphasis focused on palliative care. Now most of the population living with HIV can expect an almost normal life expectancy of good quality, providing they are able to access and adhere to HAART. Historically there had been a reticence to transfer individuals with HIV to more intensive/critical care settings, but the introduction of HAART along with effective treatments for serious HIV-related conditions in those not yet on HAART has changed clinical practice.
The care of patients with HIV
This is provided by a multidisciplinary team. Prescription of HAART may be complicated by HIV resistance, drug administration (particularly the paucity of intravenous [IV] options), and pharmacokinetics; thus, antiretroviral (ARV) regimens should not be altered without the advice of an HIV clinician and pharmacist. Particular attention should be paid to complex drug–drug interactions (more information can be obtained at http://www.hiv-druginteractions.org/). 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 centre.
As the prognosis for individuals living with HIV has improved, increasingly patients are affected by non-HIV comorbidities, including cardiovascular disease, liver disease, and other chronic conditions. These patients may present with the particular challenges in common with an ageing ICU population. The increased rate of oncological diagnoses (especially non-Hodgkin’s lymphoma) and subsequent exposure to chemotherapeutic regimens predisposes this patient population to neutropaenic sepsis, often requiring critical care support. The management of these conditions should not differ from that of the HIV-negative population. Within this section, we will discuss the general management of HIV-infected individuals in the critical care setting, focusing upon opportunistic infections.
HIV testing in the critical care setting
A significant proportion of individuals admitted to the ICU are unaware of their HIV status. Obtaining informed consent is often impossible. HIV tests are often performed in ‘the patients’ best interests’. If an HIV test result is likely to alter a patient’s immediate management then testing should be performed. Low CD4 counts are often seen in the critically ill, irrespective of HIV status, and should not be considered a short cut to a probable HIV diagnosis.
Antiretroviral therapy in the critically ill patient
There is limited information about the introduction of HAART in the ICU setting. There is some concern regarding the immune reconstitution inflammatory syndrome, a paradoxical worsening of an individual’s clinical state as the immune system is restored, but in most circumstances this is likely to be outweighed by the benefits of prompt antiretroviral therapy initiation. HAART administration may be difficult with limited IV options. Enteral administration of ARVs may lead to inadequate plasma levels. Drug–drug interactions are common, e.g. coadministration of the protease inhibitor atazanavir with antacids significantly reduces its plasma level. This issue has been substantially reduced with the introduction of integrase inhibitors—either raltegravir or dolutegravir-based therapies. Renal or hepatic insufficiency may also complicate the use of ARVs.
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-related condition. In those admitted with an AIDS-defining illness or with a CD4 count <200 cells/mm3, prophylaxis against opportunistic infections and rapid introduction of HAART should be considered. If the individual develops immune reconstitution inflammatory syndrome, ARVs are usually continued. Corticosteroid therapy may be required.
Pneumocystis jiroveci pneumonia
Historically, the most common reason for HIV-related critical care has been respiratory failure. While bacterial pneumonia and TB are important causes of compromise in this population, Pneumocystis jiroveci pneumonia (PCP) remains a major cause of morbidity, often requiring assisted ventilation. These patients are prone to pneumothoraces, especially if pneumatocoeles are present. Ventilatory measures should be considered with care and any sudden deterioration should prompt consideration of this complication
Typically a dry cough, increasing dyspnoea, and pyrexia. There may be few or no chest signs despite significant disease.
Chest X-ray may be normal in up to 50% of individuals or show perihilar shadowing with diffuse interstitial infiltration—‘ground glass’ shadowing. Pneumothoraces may be present. Arterial blood gas indicates the disease severity and guides management. In the less sick, exercise oximetry is useful, and a drop in oxygen saturation to <90% after 10 min on an exercise bicycle is suggestive of PCP. Induced sputum should be sent for immunofluorescence or polymerase chain reaction as per local policy. If negative, consider bronchoscopy.
If arterial partial pressure of oxygen (PaO2) <8 kPa, commence IV methylprednisolone 40 mg qds. First-line therapy is IV co-trimoxazole 3840 mg bd (unless <60 kg when dose should be adjusted to 60 mg/kg bd) for 14–21 days. Side-effects of nausea are common and pre-emptive antiemetics should be prescribed. Rash, bone marrow suppression (BMS), hepatotoxicity, and nephrotoxicity may be observed. Monitor full blood count, urea and electrolytes, and liver function tests closely. Second-line therapy, instigated due to side-effects or failure, comprises IV/oral clindamycin 600 mg qds and oral primaquine 300 mg od. Clindamycin is linked to diarrhoeal episodes (exclude C. difficile) and hepatotoxicity. Primaquine may cause nausea, methaemoglobinaemia, haemolytic anaemia, and BMS. Again, monitor bloods and assess glucose-6-phosphate dehydrogenase (G6PD) levels. Alternative agents include dapsone and trimethoprim, pentamidine, and atovaquone. Secondary prophylaxis is required post-treatment.
Negative serum cryptococcal antigen (CrAg) excludes the diagnosis. Following a computed tomography (CT) head, urgent lumbar puncture (LP), including measurement of cerebrospinal fluid (CSF) opening pressure, should be performed. If the opening pressure is >25 cmH2O, CSF should be drained until <20 cmH2O or 50% of the initial pressure. Daily (or more) LPs may be required, and a ventriculoperitoneal shunt may be necessary. CSF CrAg is positive in cryptococcal meningitis. Negative CSF CrAg, with positive serum CrAg, indicates cryptococcosis, and individuals should be treated with fluconazole to prevent meningitis. Indicators of a poor prognosis include raised intracranial pressure (ICP), decreased level of consciousness, CSF CrAg ≥ 1:1024, low CSF white cell count, and positive serum cryptococcal blood culture.
First-line therapy is IV liposomal amphotericin. Give a test dose of 1 mg in 100 ml of normal saline and monitor for adverse events. Systemic symptoms such as fever, chills, myalgia, headache, and anaphylaxis may occur. Chlorphenamine 10 mg IV, paracetamol, and hydrocortisone 25–50 mg IV given pre-emptively may alleviate these symptoms. Initial treatment is amphotericin 4 mg/kg/day following the test dose. Further side-effects include nephrotoxicity, hypokalaemia, hypomagnesaemia, hepatotoxicity, and thrombophlebitis. Again, blood parameters, including calcium and magnesium, should be monitored closely. There is now evidence that individuals should receive flucytosine 100 mg/kg/day in addition to the amphotericin. Administration requires initially daily blood monitoring, in particular for myelosuppression (which can be irreversible), hepatotoxicity, and renal impairment. Gastrointestinal and central nervous system (CNS) side-effects are also not uncommon. Skin reactions, including toxic epidermal necrolysis, are reported. Flucytosine trough levels should be monitored. Second-line therapy is comprised of fluconazole with or without flucytosine. Secondary prophylaxis with fluconazole will be required following treatment until there is significant immune restoration under HAART.
Commonly headache, pyrexia, and confusion ± focal neurology. The main differential diagnosis is primary cerebral lymphoma. In practice, diagnosis is often retrospective, indicated by a radiological and clinical improvement following 2 weeks of specific antitoxoplasmosis therapy.
Negative serology (titre <1:16) implies that toxoplasmosis is unlikely but not impossible, especially at low CD4 counts. Raised titres or presence of immunoglobulin (Ig)M are not diagnostic of acute infection, but indicate reactivation potential. Magnetic resonance imaging (MRI) brain scan should be performed, classically revealing characteristic multiple ring-enhancing lesions. Space-occupying lesions may preclude LP. If performed, results are often normal, or a slight elevation of protein ± mononuclear pleocytosis may be seen.
Oral/IV sulfadiazine 2 g qds (if patient weighs >70 kg) with oral pyrimethamine 75 mg od (after a loading dose of 200 mg) and oral folinic acid 15 mg od. Side-effects include nausea, vomiting, rash, crystalluria, hepatotoxicity, and BMS. Monitor bloods closely. Second-line therapy is oral clindamycin 600 mg qds, oral pyrimethamine, and oral folinic acid 75 mg od. Adverse events include rash, hepatotoxicity, and BMS.
Approximately 80% of patients should respond to anti-Toxoplasma treatment. The majority will experience a radiological and clinical improvement within 14 days.
An estimated 300–500 million people contract malaria annually and at least three quarters of a million die. Global travel has contributed to the growing incidence of malaria in developed countries such that it is the most common cause of severe imported infection in non-endemic areas, and the impact is compounded by the increasing incidence of drug-resistant Plasmodium falciparum malaria. There are four types of malarial parasite affecting man; however, severe malaria is caused almost invariably by P. falciparum infection—obligate intraerythrocytic protozoa that are primarily transmitted by the infected female Anopheles mosquito.
Malaria must always be suspected in any patient with unexplained fever or clinical deterioration who has returned from an endemic area. Falciparum malaria usually presents within 3 months of return, but this may be longer in those who have taken chemoprophylaxis or partial treatment. Incubation for non-falciparum malaria may sometimes be greater than 6 months. The risk of severe falciparum malaria developing is greatest among young children and visitors (of any age) from non-endemic areas.
The mainstay of diagnosis is microscopic examination of thick and thin blood films. Thick films have a higher sensitivity for diagnosis while thin films allow more accurate speciation and quantification of parasitaemia. Rapid malaria antigen testing is useful in diagnosis but can lead to false negatives and does not allow parasitaemia to be quantified.
Patients are considered to have complicated malaria if they have one or more of the underlying features:
• A parasitaemia of >5% (>2% if imported from low-intensity transmission area).
• Altered consciousness or convulsions.
• Hypoglycaemia (<2.2 mmol/l).
• Severe normocytic anaemia (haemoglobin <5 g/dl).
• Disseminated intravascular coagulation or spontaneous bleeding.
• Acute kidney injury.
• Haemoglobinuria (without G6PD deficiency).
• Pulmonary oedema or acute respiratory distress syndrome (ARDS).
• Metabolic (lactic) acidosis (lactate >5 mmol/l).
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 respiratory distress are more frequent. While a parasite density >5% and the presence of schizonts in a peripheral blood smear are associated with severe disease, semi-immune individuals in highly endemic areas may have parasite densities of 20–30% in the absence of clinical symptoms, so clear correlation between counts and outcome is difficult to make. At any level of parasitaemia, the prognosis is worse in those with higher proportions of mature parasites (mature trophozoites or schizonts containing pigment). Where malaria is diagnosed, other concurrent infections must also be pursued.
The parasite (and schizont) count should be monitored at least twice a day initially. Patients with severe malaria as well as those unable to tolerate oral therapy should be given parenteral treatment, ideally with artesunate (2.4 mg/kg 12-hourly for three doses then daily for a total 7-day course). Artesunate is a derivative of artemisinin and has been shown to reduce mortality significantly in two large randomized trials when compared to the previous first-line treatment, quinine. In the UK, few hospitals regularly stock IV artesunate and national supplies have been limited with distribution following a hub-and-spoke system from specialist centres.
Quinine-based options include: IV quinidine gluconate 10 mg/kg loading dose (maximum 600 mg) over 1–2 h, then continuous infusion of 0.02 mg/kg/min or IV quinine dihydrochloride 20 mg salt/kg loading dose over 4 h followed by 10 mg/kg over 2–4 h every 8 h (maximum 1800 mg/day). Patients who have received mefloquine or other quinine derivatives within the previous 12 h should not receive a loading dose. Changes in the volume of distribution mean doses need to be reduced by 33–50% after 2 days. Some centres monitor quinine levels daily. Cardiac monitoring is required during IV infusion, and hypoglycaemia is a significant risk, especially as malaria is associated with hyperinsulinaemia.
In addition to artemisinin/quinine-based therapy, effective treatment requires the administration of additional antimalarials. Options include doxycycline, clindamycin, and mefloquine. Early involvement of an infectious diseases/tropical medicine specialist is essential.
Patients with severe falciparum malaria must be admitted to a critical care area for full monitoring, including cardiac telemetry and blood glucose. Fluid therapy should be carefully titrated to optimize organ perfusion, as a tendency for capillary leak and thus a greater risk of ARDS and cerebral oedema means that excessive fluids could be harmful. Intubation and mechanical ventilation may be indicated not only in those with respiratory failure but also as part of airway protection for cerebral malaria to prevent hypercapnia and a subsequent rise in ICP.
An LP should be performed in comatose patients to exclude bacterial meningitis. The opening pressure is usually normal in adults; CSF is clear, with <10 white cells/µl, and the protein is often slightly raised. Malaria itself is only associated with mild neck stiffness; neck rigidity and photophobia are absent. Other associated or nosocomial infections should also be sought and treated as these are not uncommon 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 haemorrhages are common; papilloedema is rare. A variety of transient abnormalities of eye movement, especially disconjugate gaze, may occur. Convulsions should be treated with benzodiazepines. A nasogastric tube should be inserted and the stomach aspirated unless airway protection has been secured.
Acute kidney injury is virtually confined to adults. The mechanisms underlying this are not well understood, although it is usually reversible. The old fashioned ‘blackwater fever’ with severe haemolysis is now very uncommon. Treatment is supportive, maintaining a good fluid balance, ensuring no evidence of obstruction, and commencement of haemofiltration, if required. Hypoglycaemia is common and should be treated with 50% glucose followed by a continuous infusion of glucose, if required. Most patients can be established on enteral nutrition early. A very common finding is a low platelet count, usually without any bleeding. This typically recovers as the parasite count falls. Disseminated intravascular coagulation is uncommon.
Exchange transfusion can be considered in P. falciparum infection when parasitaemia is >10% and in patients with coma, renal failure, or ARDS, regardless of the level of parasitaemia, although there is not any strong evidence to support this. The risks of exchange transfusion are likely to outweigh the benefits in all but the most refractory of circumstances.
Studies of antipyretics, anticonvulsants (phenobarbital), heparins, anticytokine/anti-inflammatory agents (e.g. anti-tumour necrosis factor [TNF] antibodies, dexamethasone, pentoxifylline), iron chelators, and hyperimmune sera have all been disappointing. Steroids have been used in cerebral malaria but have been associated with a worse outcome than quinine alone.
Extremes of age, seizures, papilloedema, deep coma, decerebrate or decorticate posturing, organ dysfunction, acidosis, respiratory distress, and circulatory collapse are all associated with a poor outcome. The mortality of untreated falciparum malaria is close to 100%. The fatality rate for treated severe malaria is 10–40%. A lower mortality rate (1–2%) has been reported for patients with severe malaria treated in European ICUs, which may be attributed to early admission to high dependency unit/ICU; it may also be that this patient group selects out those prone to early cerebral malaria.
Vasculitides are a heterogeneous group of relatively uncommon diseases characterized by the presence of inflammatory cells in the blood vessel wall and damage to vessel integrity. These, in turn, may cause bleeding and narrowing of the vessel lumen, leading to tissue ischaemia and necrosis. Systemic necrotizing vasculitides are potentially life-threatening conditions involving multiple organ systems. Their ICU outcome is poor, with in-hospital mortality of >50%.
1 Reproduced from Arthritis & Rheumatism, 65, Jennette, J. C., Falk, R. J., Bacon, P. A., et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, pp. 1–11. Copyright (2013) with permission of John Wiley and Sons.
The Chapel Hill Consensus Conference (CHCC) of 1994 (reconvened in 2012) categorized systemic vasculitides depending on the size of the vessels involved.1 CHCC2012 revised 1994 definitions and following categories are recognized:
1. Large vessel vasculitis, e.g. giant cell arteritis, Takayasu arteritis.
2. Medium vessel vasculitis, e.g. polyarteritis nodosa, Kawasaki disease.
3. Small vessel vasculitis, e.g. Wegener’s granulomatosis, microscopic polyangiitis, pauci-immune rapidly progressive glomerulonephritis, Churg–Strauss syndrome (CSS), antiglomerular basement membrane diseases, Henoch–Schönlein purpura, cryoglobulinaemic vasculitis, hypocomplementaemic urticarial vasculitis. Small vessel vasculitides sometimes have medium vessel involvement as well; they are commonly associated with antineutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) or proteinase 3 (PR3); they are associated with high risk of glomerulonephritis and respond best to immunosuppression with cyclophosphamide. ANCA binding to the molecules on activated neutrophils is thought to be an important mechanism of injury in these conditions.
4. Single organ vasculitis, e.g. CNS vasculitis, cutaneous leukocytoclastic angiitis, cutaneous arteritis, etc.
5. Variable vessel vasculitis, Behçet’s disease, Cogan’s syndrome.
6. Vasculitis with probable aetiology, hepatitis C-associated cryoglobulinaemic vasculitis, drug-associated ANCA-associated vasculitis, etc.
Goodpasture’s syndrome and secondary vasculitis due to systemic lupus erythematosus, rheumatoid arthritis, polymyositis, scleroderma, etc. are other vasculitic conditions. CNS vasculitis and Cogan’s syndrome, etc. are much less common diseases.
Incidence, outcome, and aetiology
In the UK, the incidence of primary systemic vasculitides is ≈20 cases/million; it occurs in later decades of life (peak incidence around 65–74 years) and has a male preponderance. The incidence in the UK ICUs is ≈0.07%, with ICU mortality of ≈35% and hospital mortality of ≈55% (Intensive Care National Audit & Research Centre, UK case-mix programme database). The majority of these cases are transferred to specialist centres for management. Sepsis and respiratory failure are common complications that increase ICU mortality.
Although direct invasion of a microorganism does cause vasculitis (e.g. rickettsial vasculitis, syphilitic aortitis, etc.), primary vasculitides arise de novo—i.e. their aetiology is unknown. However, secondary vasculitides arise in association with an established disease such as rheumatoid arthritis, infections (hepatitis, HIV, syphilis), drugs (sulfonamides, penicillins, thiazides), and malignancy. Vasculitides are often associated with life-threatening complications, e.g. glomerulonephritis, diffuse alveolar haemorrhage (DAH), etc.
Presentation and diagnosis in ICU patients
A patient with known vasculitis may be admitted to the ICU as a consequence of the disease, e.g. respiratory failure due to DAH or acute kidney injury. However, initial diagnosis of vasculitis may be made for the first time after ICU admission in many patients. Thus diagnosis is often challenging because of variable and multifaceted presentation, low incidence of vasculitis in the general and especially ICU population, and overlap of signs and symptoms with a variety of common illnesses such as sepsis. Vasculitides mimic commonly occurring critical illnesses.
Signs and symptoms
Patients may present to the ICU with respiratory failure and non-specific chest radiographic changes rather than classical renal failure. Most of the signs and symptoms are non-specific and overlap with those of infections, sepsis, connective tissue disorders, and malignancies. In patients with known vasculitis and who deteriorate clinically, identifying the cause of deterioration can be equally difficult. A high index of suspicion and awareness, combined with a thorough review of history and detailed clinical examination, are key to early diagnosis. History may highlight conditions such as hepatitis (associated with polyarteritis nodosa), non-specific illness often diagnosed as infection, low-grade fever, cough, breathlessness, anaemia, headaches, a previous history of vasculitis, etc. Clinical examination may reveal evidence of the vasculitic process: nailfold infarcts, splinter haemorrhages, retinal haemorrhages, 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 or foot drop, paraesthesia, numbness, etc. occurring in two or more peripheral nerve distributions). There may be an unusual constellation of signs and symptoms involving multiple organ systems, either simultaneously or over time. In summary, vasculitides present in a variety of ways and no single list of signs and symptoms can be proposed for diagnosis. Detailed clinical findings in each condition are given elsewhere (see Further Reading).
Routine blood tests show non-specific changes such as a normocytic or microcytic anaemia, a neutrophil leukocytosis and occasionally eosinophilia (in CSS). Erythrocyte sedimentation rate (ESR; rarely measured in ICU patients) and C-reactive protein (CRP) levels are both raised. Low serum albumin and raised alkaline phosphatase, urea, and creatinine may be present. Urine examination may show blood and protein on dipstick test. In addition, viral serology, serum cryoglobulins, and blood cultures should be ordered.
ANCAs are important adjuncts in the diagnosis of ANCA-associated vasculitides, where ANCA positivity is common but not universal. Two types of assays for ANCA are in common use (indirect immunofluorescence and enzyme-linked immunosorbent assay [ELISA]). Cytoplasmic ANCAs (c-ANCAs) are primarily associated with antibodies directed against PR3 found in azurophilic granules of neutrophils and lysosomes of monocytes, whereas perinuclear ANCAs (p-ANCAs) are commonly associated with those directed against MPO, also found in azurophilic granules. If immunofluorescence alone is used, then c-ANCA is more specific for vasculitis than p-ANCA. All serum that is ANCA-positive should be tested in PR3 and MPO ELISAs as this increases their specificity. A negative ANCA does not exclude the possibility of vasculitis, as there are some small vessel vasculitides that are ANCA-negative. Principles in relation to clinical utility of ANCA testing are:
• Positive ANCA serology is extremely useful in suggesting the diagnosis (often >95% specific).
• Positive immunofluorescence assays without confirmatory ELISA for PR3 or MPO are of limited value.
• Negative assays do not exclude vasculitis.
• Persistent ANCAs in the absence of clinical features of active disease do not require continuation of treatment.
• In ANCA-positive patients, persistent ANCA negativity during remissions is reassuring but is no guarantee of disease quiescence.
• ANCA positivity, following clinical quiescence (and ANCA negativity) indicates a risk of flare-up.
A plain CXR may show non-specific changes, nodular, or cavitating lesions. Diffuse ground glass opacification should raise suspicion of DAH and vasculitis. High-resolution CT may help, but features remain non-specific.
Histopathology is the gold standard for diagnosis in most patients; biopsy of the lesions in the affected organs is desirable. Biopsies may be obtained from skin or nasopharyngeal lesions (if present) in Wegener’s granulomatosis and microscopic polyangiitis. If no easily accessible lesions are seen, then the clinical picture decides the next most appropriate site for biopsy. In most cases in the ICU, a renal or lung biopsy may be most appropriate. Percutaneous renal biopsy may show focal, segmental necrotizing glomerulonephritis without immune deposits (pauci-immune), and this generally reflects a systemic vasculitis. When lungs are involved, open lung or thoracoscopic biopsy provides a higher diagnostic yield than transbronchial biopsy.
No single test is capable of distinguishing between or even diagnosing various forms of vasculitides; a combination of history and clinical examination as well as serological, histopathological, and radiological tests are required to make a final diagnosis.
Early and rapid identification of the vasculitic process and early treatment cannot be overemphasized. Delayed therapy can result in increased morbidity and, sometimes, mortality. The severity of disease dictates the intensity of initial treatment, which in turn is often directly associated with risk of treatment-related complications such as sepsis.
Immunosuppression with a combination of high-dose corticosteroids and cyclophosphamide is the most commonly used first-line treatment for active generalized disease. Remission in Wegener’s granulomatosis and microscopic polyangiitis has been reported to be up to 90%; this may be less so in the critically ill. Trial of corticosteroids alone can be considered for Churg–Strauss syndrome, polyarteritis nodosa, and conditions that are not immediately life-threatening. Although both drugs are usually given orally, in the critically ill, the IV route is preferred as there may be uncertainty about gastric absorption. There is evidence that pulsed IV cyclophosphamide is as effective in obtaining remission as oral therapy and may be less toxic; however, continuous oral therapy has less risk of relapses as against pulse IV therapy. For the patient in the ICU with fulminant multisystem disease, methylprednisolone is given IV in three daily doses (total daily dose of 0.25–1.0 g) for 3–5 days followed by 1 mg/kg oral prednisolone or equivalent. Cyclophosphamide (0.5–1 g/m2 body surface area) IV is given at the same time and repeated at 1–4-weekly intervals; lower doses are used in the elderly and those with renal insufficiency. Alternatively, 2–4 mg/kg of oral cyclophosphamide is used if gastric absorption is assured. Azathioprine, methotrexate, and leflunomide are effective maintenance therapy drugs. They may be substituted for cyclophosphamide at 3 months to reduce complications of therapy.
Plasmapheresis may be used as an adjunctive therapy in addition to immunosuppression; although its role is far from clear, it is effective in renal vasculitis. This may be tried in rapidly progressive glomerulonephritis or DAH. It may also improve renal recovery in rapidly progressive glomerulonephritis although offers no survival advantage over immunosuppression.
Because of the complications and morbidity associated with steroids and cyclophosphamide, alternative therapies with rituximab and mycophenolate mofetil are equally effective. Levamisole and TNF-α inhibitors have been used recently. Many newer therapies and immunosuppressants are being trialled. There are several case reports of benefit of activated human factor VII in cases of DAH. IV immunoglobulins in a single dose may be beneficial in Kawasaki disease in children.
Specific ICU management
The management of these patients in the ICU is supportive in addition to specific immunosuppressive therapy. A few points are worthy of mention:
• Wegener’s granulomatosis involves upper airways and patients may have subglottic stenosis, making intubation potentially difficult. An endotracheal tube of smaller diameter may be needed and tracheostomy may be required in many.
• DAH and massive pulmonary haemorrhage increase early mortality. Lung-protective ventilation may reduce lung injury and allow DAH to resolve. Permissive hypercapnea may be beneficial.
• Cardiovascular management may require invasive monitoring to keep patients on the ‘drier’ side while avoiding complications. This will reduce pulmonary oedema and may help in reducing DAH.
• Many patients will develop acute kidney injury and may require renal replacement therapy. This may be temporary, but the majority of patients will require long-term renal replacement therapy and will progress to end-stage renal disease.
• Sepsis must be aggressively treated, as one of the common complications of immunosuppressive therapy is infection.
• Other supportive measures include adequate nutrition, tight control of blood sugar, deep vein thrombosis prophylaxis, etc.
In patients who fail to show the expected response to immunosuppression, the possibility of ‘vasculitis mimics’ must be considered and therapy modified (e.g. sepsis, endocarditis, hypercoagulable states, fungal cavitating diseases of lung, malignancy).
Vasculitides are very rare in the ICU and have a high mortality. Some ICUs may never admit such patients as they are usually referred to larger centres. Delays in diagnosis of vasculitides 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 diagnosis 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 ANCA-associated vasculitides, will speed the diagnostic process and start of therapy.
The reported incidence of severe sepsis in critical care units varies between countries in the developed world. Despite a steady fall in hospital mortality over the past few decades the actual number of deaths has risen, probably as a result of increasing age and the number of comorbidities of patients. Using Consensus Conference definitions it is estimated that between 20% and 50% of patients with severe sepsis will die. A significant proportion of patients will be admitted because of their infection, whilst others will acquire it during their stay. Respiratory and abdominal infections are the most common cause of severe sepsis, closely followed by urinary tract, soft tissue, and primary bloodstream infection. Surgery is not the only option when considering source control; the benefit of any intervention must be balanced against the inherent risk of performing the procedure itself and any associated complications.
Prevention is better than cure—the following (not exhaustive) should always be considered:
• Aseptic technique.
• Eradication therapy.
• MRSA to prevent colonization.
• Selective decontamination of the digestive tract (SDD) to reduce risk of VAP.
• Isolation of infected patients.
• Closed suction of the respiratory tract.
• Wall washing.
• Damp dusting.
• Microbiological surveillance.
These are usually incorporated into local policy. Some are common sense, some have strong evidence, and some do not.
Any infective process may fuel an inflammatory response and may result in severe sepsis and multiorgan failure. The source may be an abscess, necrotic tissue, contamination secondary to a perforated viscus, or an infected foreign body, e.g. in-dwelling catheter. In broad terms, source management may involve:
• Surgical/percutaneous drainage.
• Catheter removal.
Recent advances in imaging and interventional techniques frequently make percutaneous management an option with a better risk–benefit profile.
The early use of appropriate antibiotics, i.e. within 1 h of recognizing severe sepsis, is advised. This approach is associated with improved survival irrespective of whether infection is suspected or confirmed (the Surviving Sepsis Campaign guidelines). It also helps with source control. Knowledge of the local ecology and resistance patterns is essential in antibiotic choice; a good working relationship with the microbiology department is vital. Protocols may be in place but these need to evolve to fit the local ecology. If non-stock antibiotics are needed, then mechanisms to allow them to be rapidly dispensed from the pharmacy will minimize delays in administration.
An abscess is a liquid-filled collection containing a variety of cells walled off from surrounding healthy tissue. It may drain spontaneously, to form a sinus or fistula, or as a result of surgical or radiological intervention. Imaging by ultrasound and CT are now both accurate and easy, and, in competent hands, can be combined with percutaneous drainage. This reduces the risk of contamination, avoids the need for an operation, and hence the complications associated with a surgical wound, e.g. wound infection, dehiscence, and pain control.
The site of the collection and severity of illness of the patient will have some bearing on the method of control, e.g. an empyema can be identified with portable ultrasound and drained via a thoracostomy tube in the ward/ICU environment. More invasive radiological or surgical intervention will require transfer of the patient to another department with the additional risks that this entails. It is important to consider unusual sources of infection, including sinus and dental collections.
Source control is secondary to appropriate resuscitation measures, but may have to occur concurrently and, indeed, may on occasion assist resuscitation. In dire circumstances where surgical drainage is necessary, the use of a temporary percutaneous drain could allow time for adequate resuscitation prior to definitive surgery.
The source of infection may be from a perforated viscus. This is likely to be identified clinically but is aided by imaging. Management will be influenced by the severity of illness of the patient, the available surgical expertise, and the site of the perforation. Options include:
• Surgery; removal of the damaged viscus, e.g. appendicectomy.
• Drain insertion.
• A proximal, defunctioning ostomy can be created.
• Damage limitation surgery, i.e. doing the minimum to eliminate the source and allow recovery before returning for definitive treatment.
The Surviving Sepsis Campaign guidelines (2013) and Guidelines for the Provision of Intensive Care Services (2015) recommend surgical source control within 12 h of identification, although a prospective study on patients with gastrointestinal perforation in 2014 suggested that source control within 6 h has a positive impact on 60-day outcome. The intervention chosen should be that which is deemed most effective with the least physiological insult, and may require multidisciplinary input.
Dead tissue is an ideal medium to support the growth of microorganisms. Debridement, if possible, is the optimal management, and timing is critical; however, there are also a variety of potential approaches in different circumstances:
• The use of special dressings.
• Applying enzymatic or other biological agents.
Often a combination of these is used. Typical radiological signs of necrosis are not always evident and, in these circumstances, particularly when the patient is critically ill, surgery is the only safe option.
In most circumstances, debridement is not required immediately and therefore there will be time to resuscitate and stabilize the patient prior to surgery, e.g. debridement for necrotizing fasciitis should be performed within 12 h, although, as a general principle, the earlier the better. There are some situations where delay is beneficial and is associated with better outcome, e.g. allowing clear demarcation between healthy and necrotic tissue to develop, during which time hyperaemia in surrounding inflamed tissue will reduce so there is less bleeding during surgery. It is for this reason that delayed pancreatic necrosectomy is associated with a better outcome.
The use of continuous peritoneal lavage may remove contaminated tissue and reduce the risk of recurrent infection. Planned relaparotomy can be facilitated by adopting an ‘open abdomen’ technique where mesh or another material is used to cover the defect temporarily. This avoids the risks associated with raised intra-abdominal pressure but can expose the patient to further infection and is labour-intensive to manage.
Infected foreign body
The most common infected foreign body in ICU is an in-dwelling CVC. It makes sense to remove an infected object but this may not always be possible, e.g. endocarditis in a prosthetic valve.
When an in-dwelling vascular catheter is suspected as a source of infection, blood for culture should be taken via the line and peripheral venepuncture. If there is any suggestion that a line has been inserted in a non-sterile way it should be replaced within 24 h. A different site should be chosen but, if the risks outweigh the benefits, e.g. a coagulopathy or burns, rewiring can be considered provided that the catheter has been in situ <72 h and there are no local signs of infection/inflammation. Tunnelled lines are less likely to become infected, and soft-tissue infection can be managed with appropriate antibiotics. There is debate as to when lines should be changed. Venous catheters should be reviewed daily and changed when there is evidence of local or systemic infection and removed as soon as they are no longer required. Local guidelines should be followed.
2. Early antibiotics/resuscitation.
3. Source identification:
• Imaging will depend on suspected site and severity of illness of patient. Seek advice from radiologist.
• If collection identified, need to identify underlying cause. May require contrast studies.
4. Source control:
• Collection should be drained (percutaneous or surgical).
• Perforated viscus could be removed or defunctioned.
• Extensive debridement within 12 h of diagnosing necrotizing fasciitis.
• Conservative/supportive management and/or peritoneal lavage if pancreatic necrosis.
• Consider surgery if negative imaging confirmed by senior radiologist, dead tissue suspected as underlying cause, and patient critically ill.
• Only change invasive lines when they are suspected as the underlying cause or there is evidence of infection, e.g. inflamed/purulent entry site.
SDD is a prophylactic protocol given early during an ICU patient’s admission, aiming to eradicate potential pathogenic microorganisms (PPMs) from the oropharynx and digestive tract of patients at risk of nosocomial infections, e.g. ventilated patients, neutropaenic patients, and neonates.
The protocol comprises a combination of administering hygiene measures, oropharyngeal, and enteral non-absorbable antimicrobials (e.g. amphotericin, colistimethate sodium, and tobramycin) as well as a short course of IV antibiotics, usually cefotaxime. Selective oropharyngeal decontamination consists of SDD without the enteral suspension and without IV antibiotics.
Once a patient has been successfully decolonized, the unaffected anaerobic flora offer prevention against new colonization with PPMs, a principle called colonization resistance.
Nosocomial infection in the ICU carries a significant morbidity burden. During critical illness, alteration of the normal gut flora and colonization of the oropharynx by enteric bacteria increase the susceptibility of acquiring nosocomial infection.
Regular microbiological screening (e.g. every 3–4 days) can be employed to assess efficacy of decontamination. The choice of therapeutic antibiotics aims to minimize interference with the native anaerobic flora by avoiding agents such as broad spectrum penicillins, hence the term ‘selective’.
The philosophy of SDD has four tenets:
1. Critical illness importantly impacts the body flora, promoting a shift from normal to abnormal carriage and from low-grade carriage to high-grade carriage, i.e. overgrowth of normal and abnormal flora.
2. Gut overgrowth (i.e. ≥105 colonies per millilitre of saliva or faeces), in particular due to abnormal aerobic Gram-negative bacilli, is a critical event that precedes endogenous infections and is a risk factor for antimicrobial resistance.
3. A limited range of 15 PPMs is responsible for the majority of infections in ICU, and SDD mainly impacts these microorganisms.
4. Most ICU infections are primary endogenous infections, followed by secondary endogenous and exogenous infections.
Potential pathogenic microorganisms (PPMs)
Pathogens have been divided into normal and abnormal PPMs. These include aerobic Gram-negative bacteria, methicillin-susceptible S. aureus, and yeasts.
• Primary endogenous: infections caused by pathogens present on admission.
• Secondary 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 which develop without preceding colonization.
• Six ‘normal’ PPMs are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Candida albicans, S. aureus, and Escherichia coli.
• Nine ‘abnormal’ PPMs are Klebsiella, Proteus, Morganella, Enterobacter, Citrobacter, Serratia, Acinetobacter, Pseudomonas spp., and MRSA.
See Table 28.1 for an example of a typical SDD protocol.
Table 28.1 Typical protocol for SDD
Length of treatment
IV antibiotics, e.g. cefotaxime 80–100 mg/kg/day
Control primary endogenous infections caused by PPMs present in the patient’s flora on admission
Enteral antimicrobials, e.g. polymixin E, tobramycin, and amphotericin (PTA) paste
Throughout ICU stay
Prevent oropharyngeal/intestinal carriage of secondary endogenous infection acquired in ICU
High level of hygiene, e.g. topical PTA paste on tracheostomy
Throughout ICU stay
Prevent exogenous infections, especially lower airway
Surveillance cultures of throat and rectum
On admission and twice-weekly
Monitor effectiveness and detect resistance
SDD has amongst the greatest bases of evidence for any practice in intensive care, comprising over 50 randomized controlled studies and over 10 meta-analyses investigating its use since 1993. Proponents cite that many of these trials point toward benefit, for instance:
1. Significant reduction in carriage and infection due to aerobic Gram-negative bacilli and yeasts.
2. Reduction in Gram-positive lower airway infections (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.34–0.78).
3. No significant reduction in carriage due to Gram-positive bacteria.
4. No increase in Gram-positive bloodstream infections (OR 1.03; 95% CI 0.75–1.41).
5. Does not significantly reduce fungaemia (OR 0.89, 95% CI 0.16–4.95), owing to the low event rate.
Despite the large evidence base, SDD is not widely practised in most ICUs other than North West Europe, in particular Holland. A survey in 2012 by the SuDDICU group found concerns amongst clinicians that:
1. Research has not adequately addressed concerns about antibiotic resistance and SDD, and consequently,
2. SDD may increase antibiotic resistance, particularly in areas with pre-existing high prevalence of drug resistance.
3. SDD may increase rates of C. difficile.
While recent reviews and meta-analyses conclude that there is no relationship between the use of SDD or selective oropharyngeal decontamination and the development of antimicrobial resistance in pathogens in patients in the ICU, there is still widespread concern that long-term ICU-level changes in resistance rates have not been adequately assessed. These concerns are being addressed with ongoing research studies.
Clinical diagnosis of infection
The diagnosis of infection is often difficult. Infection triggers a host inflammatory response, and changes in heart rate, respiratory rate, blood pressure, temperature, and leukocyte count may simply reflect non-infectious systemic inflammation. These changes are neither specific nor sensitive for infection in critical illness.
Sepsis, the most serious clinical manifestation of infection, is caused by the dysregulated host response to infection. In clinical practice sepsis is a syndrome defined by non-specific alterations in physiology. Consensus definitions such as Sepsis-3 and the systemic inflammatory response syndrome (SIRS) attempt to improve the consistency, sensitivity, and specificity of sepsis diagnosis, but these definitions lack specificity to discriminate infection. Confirmation of infection is still largely dependent on the isolation and culture of infectious organisms. This takes time and lacks sensitivity.
The absence of sepsis-specific biomarkers compounds the diagnostic challenges and contributes to delays in the administration of appropriate antimicrobials and the use of unnecessary antimicrobial agents.
The ideal biomarker of infection
The ideal marker of infection should accurately diagnose infection, differentiating between infectious and non-infectious causes of inflammation. It should be inexpensive, technically straightforward to use, shorten the time to diagnosis, differentiate between viral, bacterial, and fungal infection, provide prognostic information, and reflect the effectiveness of treatments such as source control and antimicrobial treatment.
None of the sepsis biomarkers currently in use fulfil these criteria, with many best described as markers of the host inflammatory response. Some have good negative predictive value (e.g. CRP, procalcitonin [PCT], and endotoxin), with low levels effectively excluding infection, but all have limited specificity in distinguishing infective from non-infective causes of inflammation. It is likely that diagnostic accuracy of individual markers is improved using a multimarker approach. Several panels of biomarkers have been investigated, such as the ‘bioscore’, comprising PCT, triggering receptor expressed on myeloid cells (TREM-1), and Cluster of Differentiation 64 (CD64), but none have yet been widely prospectively validated.
Gene expression profiling (transcriptomics), the study of proteins produced by the genome (proteomics), and cellular metabolites (metabolomics) will allow greater characterization of the host response to infection in the future and will facilitate rapid non-culture-based identification of microorganisms. These techniques are not yet established in routine clinical practice.
Markers of the host response to infection
Fever (temperature >38.3°C) complicates up to 70% of ICU admissions. While the source of fever is often due to infection, it may be non-infectious (e.g. pancreatitis, burns, seizures, vasculitis, pulmonary embolus, myocardial infarction, malignancy, acalculous cholecystitis, drug reaction or withdrawal, transfusion reaction, neuroleptic malignant syndrome, malignant hyperthermia, and thyrotoxicosis). The magnitude of fever may help differentiate the cause: fevers >41°C are usually non-infectious; fevers between 38.9°C and 41°C are likely to be infectious; fevers between 38.3°C and 38.8°C may be infectious or non-infectious.
White cell count and differential
Infection commonly causes a rise in total white cell count (WCC; leukocytosis). Leukocytosis (>11 × 109/l in adults) is most commonly because of an increase in the absolute number of neutrophils (neutrophilia; >7.7 × 109/l) but can occur with an increase in lymphocytes, eosinophils, monocytes, or basophils. Severe infection can suppress normal bone marrow function, resulting in leukopenia (<4 × 109/L) and the release of immature (band form) neutrophils into the circulation. The consensus definition of SIRS includes a criteria of WCC >12 × 109/l or <4 × 109/l or >10% immature neutrophils in the circulation, but this is neither sensitive nor specific for infection.
(WCC >11 × 109/l and neutrophils >7.7 × 109/l) is commonly seen in infection, but is poorly specific as it is also seen in pregnancy, following tissue damage, stress, inflammation, corticosteroid therapy, and in myeloproliferative disease.
(WCC >11 × 109/l and eosinophils >0.5 × 109/l) is associated with allergic reactions (e.g. asthma, hay fever, and drug reaction) and parasitic infection, notably protozoal and helminth infection.
(WCC >11 × 109/l and lymphocytes >4.8 × 109/l) is associated with acute viral infections, particularly cytomegalovirus, Epstein–Barr virus, hepatitis, and HIV infection. It is also seen in chronic intracellular bacterial infection (e.g. tuberculosis, brucellosis) and some protozoal infections (e.g. toxoplasmosis, trypanosomiasis).
(WCC >11 × 109/l and monocytes >0.8 × 109/l) may be seen in acute and chronic monocytic leukaemia and bacterial infections such as tuberculosis and infective endocarditis.
Erythrocyte sedimentation rate (ESR)
The ESR is the rate (mm/h) at which erythrocytes suspended in plasma settle. It is an indirect measure of the concentration of prosedimentation factors in the acute phase response, most notably fibrinogen. ESR is a non-specific marker and is raised in most causes of local and systemic inflammation, infection, tissue injury, malignancy, and trauma. The lack of specificity for infection coupled with a slower response time than other markers (e.g. CRP) limit its utility in critical care.
C-Reactive Protein (CRP)
CRP is an acute phase plasma protein, synthesized and released by the liver in response to proinflammatory cytokines, notably interleukin (IL)-6. Part of the innate immune response, CRP has a number of roles, including complement activation, pathogen opsonization, and modulation of inflammation and coagulation. CRP rises rapidly (6–8 h) in response to infection, inflammation, and trauma, peaking at 48 h. As a sensitive but non-specific marker of inflammation, CRP is frequently used as a screening test for infection and, with serial measurements, to monitor the resolution of inflammation following treatment. Questions remain regarding the predictive value of CRP as a biomarker of infection in critical care. CRP concentration at ICU admission appears to correlate with severity of illness (organ dysfunction, ICU length of stay, and mortality), and several studies have shown higher levels in patients with proven infection compared to non-infected patients. Very high levels of CRP (>500 mg/l) are strongly associated with bacterial infection, but, with more modest increases, the specificity of CRP is limited. There is no clear threshold for diagnosing infection. The specificity of CRP for diagnosing infection increases if combined with high temperature (>38.2°C).
PCT is the precursor of the hormone calcitonin. In the absence of infection, PCT is produced almost exclusively by the neuroendocrine C cells of the thyroid, with almost undetectable (pg/ml range) levels in serum. Following bacterial infection, non-neuroendocrine tissue expression of PCT increases significantly and serum levels increase rapidly (3–6 h). The kinetics of the response of PCT to infection appear more favourable than those of CRP, with a more rapid rise and constant half-life (approximately 24 h) once infection is controlled. The magnitude of rise in PCT appears related to severity of illness and the likelihood of bacteraemia, with low levels predicting the absence of bacteraemia. The increase in PCT with fungaemia is less consistent, therefore limiting the diagnostic value of PCT in fungal infection. Although less likely than CRP to be elevated in patients with non-infectious systemic inflammation, PCT is increased in a number of non-infectious disorders (e.g. trauma and surgery) and cannot be regarded as a specific biomarker of infection in critically ill patients. Whether PCT is more sensitive and specific than CRP for the diagnosis of infection remains debated.
In pneumonia, PCT levels correlate with severity of illness and differentiate between bacterial and viral infection and the risk of bacteraemia. Treatment algorithms incorporating PCT-based thresholds for treatment of respiratory tract infection reduce antibiotic use with no apparent increase in mortality. The role of PCT in antibiotic stewardship in critical care is supported by systematic review and meta-analyses but requires further validation. With current trends toward shorter duration antimicrobial courses, the added benefit of PCT-guided discontinuation of antibiotic therapy remains unclear.
Microbial pathogen-associated molecular patterns, such as endotoxin and peptidoglycan, activate the host immune response by binding to cell membrane toll-like receptors and cytoplasmic pattern recognition receptors. This activates the transcription factor nuclear factor kappa B (NF-κB), leading to upregulation of a number of proinflammatory cytokines, notably IL-6, IL-8, IL-1β, and TNF-α. Levels of proinflammatory cytokines rise within 1 h of infection and have some value in the assessment of the inflammatory response, but this response also occurs following a number of non-infectious proinflammatory stimuli and is not specific to infection. IL-6 is reliably measurable in plasma and has received most attention as a biomarker in sepsis. Although lacking specificity as a diagnostic biomarker, IL-6 appears to have some prognostic value in sepsis, with levels correlating with increasing mortality. A combined cytokine score, comprising IL-6, IL-8, and the anti-inflammatory IL-10, has been shown to correlate with survival with a predictive value greater than CRP and PCT.
Leukocyte cell surface markers of infection
Proinflammatory cytokines upregulate the expression of a number of proteins by neutrophils, macrophages, and monocytes. A number of these proteins, either on the cell surface or in soluble form, have been investigated as biomarkers of sepsis, including cluster of differentiation 64 (CD64), triggering receptor expressed on myeloid cells 1 (TREM-1), receptor for advanced glycation end products (RAGE), CD11b, CD14, and heparin-binding protein.
CD64 is a high-affinity receptor for the Fc portion of immunoglobulin. Neutrophil expression of CD64 increases significantly following infection. Initial studies in critically ill adults suggest that CD64 levels correlate with severity of illness in sepsis and have greater specificity for discriminating infection than PCT. CD64 also shows promise as a useful biomarker of sepsis in neonates, with sensitivity and specificity for diagnosis of infection >70% in this cohort.
TREM-1 is a member of the immunoglobulin superfamily expressed on the surface of myeloid cells. TREM-1 amplifies the toll-like receptor-initiated response to microbial infection and potentiates the release of proinflammatory cytokines. The released form, soluble TREM-1 (sTREM-1), has been recognized as a potential surrogate marker of infection in sepsis with serum levels rising rapidly following bacterial or fungal infection and correlating with illness severity. However, more recent studies have demonstrated increased sTREM-1 expression in a number of non-infectious inflammatory disorders such as pancreatitis, postcardiac arrest, and following cardiac and abdominal surgery. Meta-analyses suggest sTREM-1 has at least moderate diagnostic accuracy as a marker of infection in patients with systemic inflammation.
sTREM-1 may be an effective marker of localized infections. Pleural sTREM-1 has been shown in a number of studies to discriminate infected from non-infected pleural effusions, and increases in CSF sTREM-1 have been shown to discriminate bacterial from viral meningitis. The role of alveolar sTREM-1 in the diagnosis of community-acquired bacterial pneumonia and VAP remains unclear. Alveolar sTREM-1 is increased in bacterial (and fungal) pulmonary infection, and several studies suggest it performs better than other clinical or laboratory tests (including CRP and PCT) in discriminating pulmonary infection. Other studies suggest lower discriminatory value.
RAGE is a transmembrane multiligand receptor that binds a variety of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1) and other proteins released from necrotic cells. RAGE-dependent activation of NF-αB plays an important role in propagating proinflammatory gene expression in sepsis. Serum levels of the soluble isoform of the receptor (sRAGE) are elevated within 24 h of the onset of sepsis in adult patients, with levels correlating with illness severity (survival, Acute Physiology and Chronic Health Evaluation [APACHE] II, and sequential organ failure assessment [SOFA]). sRAGE levels appear similarly predictive of survival in community-acquired pneumonia. What remains unclear is whether sRAGE is a specific biomarker for infection in the context of sepsis or whether it might more accurately be considered a biomarker of lung injury. Alveolar epithelial type I cells are known to express RAGE, and plasma sRAGE has been validated as a marker of alveolar epithelial injury in patients with hydrostatic pulmonary oedema and those with, or at risk of, ARDS. In a retrospective study of adult patients with severe sepsis, sRAGE was able to discriminate those patients who developed ARDS from those who did not.
Microbial products as a marker of infection
Endotoxins are lipopolysaccharides (LPSs) that form an essential component of the cell membrane of Gram-negative bacteria. Endotoxin is a pathogen-associated molecular pattern and a principal trigger of innate immunity and the host response in Gram-negative sepsis. Reliable measurement of endotoxin is challenging and the utility of endotoxin as a biomarker of infection is limited. Endotoxaemia is common in critical illness, occurring in more than half of patients. Endotoxin activity level does appear to correlate with likelihood of developing sepsis, illness severity, and risk of Gram-negative infection, but only a small proportion of patients with elevated endotoxin levels have microbiologically proven infection, limiting the specificity of endotoxin as a marker of infection. Endotoxin does appear to have strong negative predictive value, with infection unlikely in the absence of elevated endotoxin levels. Lipopolysaccharide-binding protein is an acute phase protein that binds LPS. Lipopolysaccharide-binding protein has been investigated as a marker of infection but has limited discriminatory value.
Exotoxins are secreted by a wide range of bacteria, with many acting as significant virulence factors e.g. C. difficile (toxins A and B); Clostridium perfringens (alpha toxin); Clostridium tetani (tetanus toxin); Clostridium botulinum (botulinum toxin); S. aureus (toxic shock syndrome toxin 1); Vibrio cholerae (cholera toxin); Streptococcus pyogenes (pyrogenic exotoxin); Corynebacterium diphtheriae (diphtheria toxin). Exotoxins can serve as markers of specific infection, with many having immunobased assays for detection.
Fungal wall components
Rapid assays are available to detect the presence of the immunogenic fungal cell wall components 1,3-β-D-glucan and galactomannan. These tests appear to have high diagnostic accuracy to discriminate patients with invasive fungal infection, notably Candida and Aspergillus. It should be noted that not all fungal species have β-glucans and galactomannan in their cell walls (e.g. Cryptococcus), limiting the utility of these assays as screening tests for fungal disease.
Detection of infectious organisms as a marker of infection
The ultimate biomarker of infection is identification of the microorganism responsible. Blood culture reflects the accepted standard for the detection of bloodstream infection and allows microbial identification and determination of antimicrobial sensitivities. However, blood culture takes time (typically 24–72 h) and lacks sensitivity, with only 30–40% of patients with sepsis having positive blood cultures. Positive results may reflect contamination or colonization, raising question of their pathophysiological relevance.
Amplification of microbial nucleic acids in positive blood cultures or other microbiological specimens (e.g. bronchoalveolar lavage fluid) using polymerase chain reaction (PCR) followed by hybridization against a microarray of microbial genes may increase culture sensitivity and reduce time to results. This is likely to be of significant benefit in the culture of fastidious and/or multiresistant organisms but remains a culture-dependent technique at present.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry is an analytical technique in which chemical compounds are ionized and then analysed according to their mass-to-charge ratio. The development of MALDI coupled with TOF analysis allows mass spectrometry to be used to identify larger biological molecules such as proteins. MALDI-TOF mass spectrometry of a microbial isolate produces a characteristic mass spectrum called a peptide mass fingerprint (PMF). Microbe identification is achieved by comparing the PMF obtained with PMFs contained in a database of known organisms. PMFs are capable of identifying individual bacterial strains, allowing early identification of antibiotic resistance. Studies have shown that MALDI-TOF mass spectrometry can be used as a rapid and reliable method for the identification of bacteria in blood cultures, urine, CSF, and respiratory tract samples. Although less established, the technique is also applicable to identification of viral and fungal infection.
Adrenal insufficiency is a condition in which cortisol synthesis, delivery, and/or uptake by tissues is compromised. It is classified into:
1. Primary adrenal insufficiency, when the adrenocortical cells are damaged or cortisol metabolism is altered.
2. Secondary adrenal insufficiency, when corticotrophin-releasing hormone or adrenocorticotrophin hormones synthesizing hypothalamic or pituitary cells are damaged.
In sepsis, the prevalence of adrenal insufficiency varies with severity of illness and may reach 60% in patients with septic shock. Critical illness is characterized by impaired clearance of cortisol.
Mechanisms of action of glucocorticoids
Glucocorticoids act through genomic and non-genomic effects.
• Genomic effects: glucocorticoids bind to a specific intracytosolic receptor. The subsequent complex may physically interact with nuclear factors, e.g. NF-αB, preventing their translocation to the nucleus and thereby inhibiting the reading of the genes for most, if not all, proinflammatory mediators. These genomic effects are indirect and are called transrepression effects. Secondly, the glucocorticoid/glucocorticoid receptor complex may migrate to the nucleus, where it will bind to the glucocorticoid-responsive element part of certain genes, upregulating the reading of these genes. In this way glucocorticoids promote the synthesis of mediators involved in the termination of inflammation. These direct genomic effects are called transactivation.
• Non-specific non-genomic effects: glucocorticoids may interact with specific membrane sites to induce non-genomic effects. For example, in the hypothalamic synaptosomes, glucocorticoids affect sympathetic modulation of cardiac and blood vessel activity, as well as the potentiation of exogenous catecholamines.
• Specific non-genomic effects: glucocorticoids release chaperone proteins in the cytosol that act on the mitogen-activated protein kinase pathway and subsequently enhance endothelial nitric oxide synthase activation.
Main effects of glucocorticoids
Glucocorticoids increase blood glucose concentrations by inducing systemic insulin resistance, liver gluconeogenesis, and glycogenolysis. They enhance lipolysis and proteolysis, providing amino acids for gluconeogenesis.
• Innate immunity: increase neutrophils, promote apoptosis of eosinophils and basophils, and improve opsonization and the activity of the scavenger system. Suppress the synthesis of inflammatory mediators such as cytokines, prostaglandins, and leukotrienes.
• Adaptative immunity: prevent differentiation of CD4+ T-cells into T-helper 1 lymphocytes, promote T-helper 2 recruitment by increasing IL-10 secretion, acting in synergy with IL-4. Thus, glucocorticoids induce a shift from a cellular toward a humoral immune response.
Glucocorticoids maintain vascular tone, endothelium integrity, capillary permeability, and myocardial inotropic activity. They are synergistic with noradrenaline and angiotensin II. In catecholamine-treated septic shock, glucocorticoids improve systemic vascular resistance and hasten shock reversal. They may also decrease the number and intensity of organ failure and ICU length of stay.
Examination: non-specific signs
• Hypotension, shock (90%).
• Fever (60–70%).
• Abdominal pain, distension (80–90%).
• Vomiting (50%).
• Confusion to coma (40–60%).
If the serum albumin <25 g/l, total cortisol levels may be unreliable; calculate free cortisol (Table 28.2).
Table 28.2 Adrenal insufficiency and random cortisol levels
If cortisol levels are low, ACTH levels can discriminate between primary (high ACTH levels) and secondary adrenal insufficiency (low ACTH levels).
250 µg of synthetic corticotrophin. The ACTH test may allow the diagnosis of adrenal insufficiency in patients with sepsis by using values of baseline and stimulated total cortisol levels following 250µg intravenous bolus of cosyntropyn.Cortisol levels >44 µg/dl or cortisol increment >16.8 µg/dl rules out adrenal insufficiency. A cortisol increment <9 µg/dl may indicate adrenal insufficiency.
Initial course of critical illness
• Fluid and vasopressor unresponsiveness with low vascular resistance and high cardiac index.
• Systemic inflammatory response syndrome with fever, tachycardia, tachypnoea.
• Multiple organ failure.
• Increased risk of death from refractory shock.
Fluid and sodium losses should be managed with fluid and vasopressors, which should be titrated to restore systolic blood pressure and tissue perfusion.
• Hydrocortisone at a daily dose of 200–300 mg in three or four IV boluses, or as a continuous infusion.
• Treatment should be continued until the clinical consequences have disappeared. If hydrocortisone was given as a bolus, there is no need to taper off. If administered as a continuous infusion, it should be tapered off by decreasing by 50% the daily dose every day. Prolonged treatment requires advice from an endocrinologist.
• Administration of fludrocortisone is optional and requires advice from an endocrinologist.
Multiple choice questions and further reading
Interactive multiple choice questions to test your knowledge on this chapter and additional further reading can be found in Appendix Chapter 28 Multiple choice questions and further reading