Infection is common in the ICU and may be the primary cause of a patient’s admission, or may occur as a secondary phenomenon in patients who are already critically ill and whose normal barriers to infection are impaired. Factors that predispose to infection in critically ill patients are shown in Box 13.1. (See also Infection control, p. 19)

It has been claimed that infection is responsible for up to a quarter of all deaths in intensive care. Early identification of developing infection, drainage / removal of septic foci and the instigation of appropriate antibiotic therapy are therefore vital.

Typical signs of infection in critically ill patients include pyrexia, tachycardia, hyperventilation (failure to wean), non-specific deterioration in overall condition and a change in inflammatory markers (rising CRP, rising or suppressed white cell count). These changes are not specific, however, and similar changes may be produced by any inflammatory process, such as those produced by endotoxaemia, ischaemia reperfusion syndromes, liver failure and pancreatitis.

It is now recognized that many processes (including infection) may trigger activation of endothelial cells, white cells, platelets and other cells, leading to the release of proinflammatory mediators, including platelet-activating factor (PAF), tumour necrosis factor (TNFα), interleukins, chemokines and other inflammatory mediators. These have effects such as increased vascular permeability (capillary leak), vasodilatation, sequestration of neutrophils, platelet adhesion and activation of complement systems. Simultaneous activation of the coagulation and fibrinolytic pathways may lead to disseminated intravascular coagulation (DIC) and failure of the microcirculation. Indeed, in sepsis, the coagulation and inflammatory pathways are inextricably linked and mutually activated.

The consequent systemic inflammatory response may range from relatively mild with minimal sequelae, to severe, resulting in multiple organ dysfunction, multiple organ failure and death.

The common definitions for sepsis, systemic inflammatory response syndrome (SIRS) and multiorgan dysfunction syndrome (MODS) were established in the early 1990s in a consensus statement from the American College of Chest Physicians and the Society of Critical Care Medicine. Although these definitions are of limited value clinically, they have been used as a means to standardize many clinical trials and have become a standard, internationally recognized nomenclature. These definitions are as follows:

Systemic inflammatory response syndrome (SIRS)

The systemic inflammatory response syndrome can be said to exist when two of the criteria listed in Box 13.2 are present, in the absence of a documented infection.

Box 13.2 Definition of SIRS

Requires the presence of two or more of the following features:

Temperature > 38°C or < 36°C

Heart rate > 90 beats / min

Respiratory rate > 20 breaths / min or PaCO₂ < 4.3 kPa

White blood count > 12000 cells / mm³ or < 4000 cells / mm³ or presence of > 10% immature neutrophils

Sepsis

Features of SIRS, together with a documented infection. The infection may be bacterial, viral, fungal, parasitic or other organism. Difficulty may sometimes arise in patients with positive cultures in distinguishing between clinically insignificant colonization and true infection (see below).

Both SIRS and sepsis may vary in severity from mild to severe, and both may progress to multiorgan dysfunction. Parallel definitions may be used, as shown in Fig. 13.1.

Fig. 13.1 SIRS and sepsis of increasing severity.

Multiorgan dysfunction syndrome (MODS)

MODS is described as abnormal function of more than one organ such that normal homeostasis cannot be maintained without intervention. In this context ‘organ’ can be taken to include the respiratory, cardiovascular and gastrointestinal systems, kidneys, liver, brain (altered conscious level), bone marrow and immune systems. MODS may respond to general supportive measures and resolution of the underlying condition, or may progress to established multiple organ failure.

In view of the similarities in the clinical picture produced by SIRS and sepsis (above), the problem may arise as how to distinguish infection. C-reactive protein (CRP) is a commonly used marker of infection but is not specific. Procalcitonin is an alternative marker that is thought to be more specific for infection, but is not yet widely available.

In general, infection is only confirmed when a positive microscopy or culture result is obtained from a normally sterile body space. Repeated samples are often required. (See investigation of unexplained sepsis, p. 334.) The time taken to obtain microbiological results varies with the particular sample type and the technique used to process it. Techniques for confirming infection, and potentially identifying the causative organism, include:

microscopy and staining (4 h)

cultures (24–48 h)

conventional PCR (48 h)

antigen tests, antibody titres, e.g. diagnosis of fungal infection esp. Candida, Aspergillus (24–48 h).

Recent international consensus guidelines on the management of sepsis in critical care have been widely adopted (Table 13.1).

TABLE 13.1 Guidelines for initial treatment of sepsis. Adapted from surviving sepsis campaign¹

1 Dellinger RP et al. 2008 Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med 36: 296–327 [published correction appears in Crit Care Med 36: 1394–1396].

While much of the evidence is low level (based on expert opinion), the recommendations also include some high level evidence, the document as a whole forms a rational and coherent approach to the management of the patient with sepsis. Central to these sepsis care bundles is the need for early effective resuscitation, early effective antibiotic therapy and source control, and where possible, the use of an appropriate ‘biological response modifier’. Currently, activated protein C, (drotrecogin alpha), is the only such agent available (see Septic shock below). The key recommendations are summarized in Table 13.1.

The clinical features are those of SIRS, with significant hypotension and end-organ dysfunction (see above). Initially patients may have a hyperdynamic circulation, with an elevated cardiac output (CO) and reduced systemic vascular resistance (so-called ‘warm septic shock’). At this stage patients exhibit warm peripheries, flushing and visible cardiac pulsation. This may rapidly progress, however, to ‘cold septic shock’ with reduced CO and cold, poorly perfused peripheries. This is frequently accompanied by marked metabolic acidosis.

The first imperatives are resuscitation and stabilization. This is followed by investigation of the underlying source of sepsis. The third stage involves management of specific underlying problems and complications.

Resuscitation and stabilization

Give high flow oxygen.

Consider the need for intubation and ventilation.

Secure venous access. (Take blood for culture and give i.v. antibiotics as appropriate.)

Give i.v. fluid challenge.

If end-organ failure is compromising respiration (respiratory failure, severe confusion, etc.), early consideration should be given to securing the airway and instituting artificial ventilation. There is a risk, however, that the drugs used to facilitate intubation may cause circulatory collapse. (See Intubation, p. 398.) Therefore, where ventilation is not required immediately, it is often wiser to institute fluid resuscitation prior to attempting intubation and to insert an arterial line to provide accurate blood pressure monitoring. If peripheral arterial cannulation is not feasible, consider femoral or brachial artery.

Patients with sepsis and septic shock are often grossly hypovolaemic because of vasodilatation and capillary permeability changes leading to third-space fluid loss. This situation may well be exacerbated by pyrexia and fluid loss related to any underlying pathology. Vigorous fluid resuscitation may therefore be required. There is controversy over whether colloid or crystalloid solutions are most appropriate. You should follow local guidelines.

Give 2–3 L fluid as initial resuscitation volume (0.9% saline or colloid).

Establish invasive monitoring, arterial line and CVP. Consider cardiac output monitoring, central venous saturation monitoring (see p. 74).

Optimize volume loading. Initially aim for a CVP 8–12 mmHg depending on patient’s condition and response, (10–15 mmHg in a ventilated patient). Above this level, it is unlikely that additional fluid loading will produce any further increase in left ventricular stroke volume index.

If there is evidence of significant myocardial depression (low MAP with high CVP; low CI or SVI where monitoring is available), consider addition of an inotrope e.g. dobutamine / adrenaline (epinephrine) to support cardiac output. (See Cardiovascular system, p. 82.)

Maintain adequate tissue perfusion pressure (MAP ⩾ 65 mmHg). If MAP remains low despite adequate volume loading and cardiac output, add a vasoconstrictor, e.g. noradrenaline (norepinephrine).

Therapeutic end points involve adequate clinical organ and tissue perfusion, e.g. warm pink peripheries, adequate urine output, mentally alert (if not sedated). Ensure all relevant microbiological investigations have been sent and appropriate antibiotics started. In cases of refractory shock:

If significant metabolic acidosis, pH < 7.1, consider bicarbonate.

If serum ionized calcium < 0.8 mmol / L, consider IV calcium chloride / gluconate.

Vasopressin infusion at physiological replacement doses. Vasopressin levels can become rapidly depleted in septic shock. Consider vasopressin as a second line vasopressor treatment. (See Optimizing perfusion pressure, p. 85.)

Functional adrenal insufficiency – low (physiological NOT pharmacological) dose steroid supplementation may be helpful, e.g. 25–50 mg hydrocortisone TDS. Seek advice and follow your local policy.

Role of haemofiltration in sepsis

There is anecdotal evidence that the clinical condition of some patients with septic shock may improve significantly when haemofiltration is commenced. This effect is independent of improvements in acid–base status and is possibly due to the removal of proinflammatory mediators. However, recent clinical trials in this area are conflicting and further trials are on-going. Seek local advice.

Role of anti-inflammatory agents

There has been a great deal of research over recent years on the use of agents to block or modulate the effects of proinflammatory mediators in the inflammatory cascade, in the hope of reducing the inflammatory response to sepsis and improving outcome. Clinical trials of anti-endotoxin antibodies, anti-TNFα antibodies and anti-PAF receptor antibodies have failed to show any benefit.

Activated protein C

A multinational trial of recombinant human activated protein C (PROWESS Trial) reported an overall 6% reduction in mortality in patients with severe sepsis. Activated protein C is now licensed and available for use in the UK. Uncertainty remains about the most effective duration of treatment. It appears to show greatest benefit in patients with a high APACHE score and does not benefit those with a score < 20 or children. Therapy with activated protein C does carry an increased risk of bleeding and many patients will have relative or absolute contraindications to its use. Patients with intracranial haemorrhage, recent stroke and multiple trauma fall into this category. Post-surgical patients should be considered on the balance of risks. Recent experience suggests that in many situations the overall balance of risks may still favour its use, and it is currently recommended as part of the Surviving Sepsis Care Bundle. At the time of writing, however, a further large multinational study testing the efficacy of the product is underway. Follow local protocols and seek senior advice.

Complications

The specific complications and pattern of organ dysfunction varies from patient to patient. Many patients require renal support, some may develop prolonged GI tract failure, and a large proportion develop ARDS or coagulopathy. Some develop multiple organ dysfunction and multiple organ failure. Specific supportive measures for each system are required (see relevant sections).

Prognosis

Overall, the mortality from severe sepsis with shock remains high, ranging from 30 to 70% in various studies. Best results are likely to be obtained by early recognition, effective resuscitation, timely source control and overall attention to detail.

Any patient in the ICU with unexplained ‘sepsis’ or rising markers of infection should have a thorough examination to identify possible sources. Appropriate microbiological samples should be obtained prior to the institution of antibiotic therapy. These should ideally include ‘clean stab’ blood cultures from a peripheral vein (in addition to cultures from any existing cannulae), sputum or BAL for microscopy and culture. Urine and any drain fluids should also be cultured. Additional investigations will be guided by the clinical picture (Table 13.2). It is important to repeat blood cultures and other microbiological investigations regularly to help make a diagnosis and to facilitate antibiotic de-escalation. (See also Distinguishing infection above.)

TABLE 13.2 Investigation of unexplained sepsis

In many cases of sepsis antibiotics are started on an empirical basis before the results of cultures and / or the sensitivity of organisms are known.

Although early appropriate antibiotic therapy is one of the few evidence-based interventions leading to improved outcome in sepsis and septic shock, prolonged use of broad-spectrum antibiotics can lead to the emergence of resistant organisms. It can also lead to the suppression of normal gut flora and has been implicated in a outbreaks of potentially lethal infections from organisms such as Clostridium difficile and MRSA. Antibiotics should be used sensibly, with due regard to their adverse effects, as well as the benefits. It is important to have a coherent policy for both antibiotic use and early de-escalation of therapy.

Table 13.3 provides a guide to empirical antibiotic therapy. You should, however, always follow your hospital antibiotic policy and / or ask advice from your hospital microbiologist.

TABLE 13.3 Empirical first-line antibiotic therapy

* If MRSA or Coag. neg. staph. possible, consider vancomycin or teicoplanin (see below)

Wherever possible the source of an infection should be eradicated. If catheter-related sepsis is suspected remove existing arterial and venous lines and send the tips for culture (see Catheter-related sepsis below). Obvious collections of pus should be drained and cultured and potentially infected wounds derided. Ensure appropriate specimens are sent to the lab. Potential means of source control are listed in Table 13.4.

TABLE 13.4 Potential means of source control

Catheter-related sepsis is a common problem on the ICU and should be considered in all patients with suspected sepsis in whom vascular catheters have been in place for more than 48 h.

Following catheter insertion, thrombus forms around the puncture site of the vessel and may propagate along the length of the catheter. This provides an excellent culture medium for bacteria, which may rapidly colonize all catheters either via the puncture site in the skin or following bacteraemia. In addition, catheters may be colonized by bacteria introduced via the access ports when the catheter is used, for example to administer drugs.

Colonization is common and does not necessarily warrant removal of the catheter or treatment. Infection is difficult to diagnose. Cultures taken through the catheter do not distinguish between colonization, infection and unrelated bacteraemia. Brush specimens taken from the lumen of the line are semiquantitive and can suggest infection. Alternatively, paired cultures can be taken from the suspect catheter and from a peripheral vein (clean stab), and the shorter time taken for development of positive cultures from the catheter used to suggest the presence of catheter-related infection.

If there is a strong suspicion of catheter-related sepsis the catheter should be removed and the tip cut off (sterile scissors) and sent for culture. In most cases, the diagnosis is made retrospectively after removal of the suspect catheter, positive tip culture and resolution of the clinical condition.

Established clot in central veins may get infected to and lead to septic thrombophlebitis. It may take a number of days to clear the infection even though the original catheters have been removed.

Ideally catheters should be replaced at a new clean puncture site.

Ideally there should be a ‘line-free’ interval between removing and replacing catheters but this is often impractical.

If necessary, provided the entry site is not obviously infected, catheters can be changed over a guide wire at the same site. This should only be considered when a clean puncture site is not available or is high risk.

The risk of line-related sepsis increases with the number of days for which lines have been present. It is unclear whether this risk is reduced by routine or ‘protocol’ line changes (see p. 386).

The risk varies significantly according to the site of cannulation (groin > jugular > subclavian).

Patients with valvular heart disease or prosthetic heart valves, intravenous drug abusers and patients with long term indwelling central venous catheters are at risk of infective endocarditis. Immune compromise may be an additional risk factor in the ICU patient.

Subacute bacterial endocarditis is a chronic form of the condition with insidious onset. Acute bacterial endocarditis (e.g. i.v. drug abusers) can lead to heart failure (disruption of normal valvular function) widespread embolic infection / infarction, and the rapid development of septic shock and multiorgan failure.

Clinical vigilance for signs and symptoms of endocarditis is important. The diagnosis should be suspected in any patient with persistent fever, unexplained positive blood cultures (characteristic organisms) and the onset of new or changing heart murmurs. Murmurs may be difficult to detect in a ventilated ICU patient. Other stigmata of endocarditis include Roth spots (retinal haemorrhages), splinter haemorrhages, Osler’s nodes (fingers), and Janeway lesions (palms). Transthoracic echocardiography is useful in patients who have developed valve dysfunction or who have a gross valvular lesion such as regurgitation or incompetence. Smaller valve lesions can however be difficult to detect using transthoracic echo, particularly when the patient is artificially ventilated (poor echo window). Transoesophageal echo (TOE) is the imaging of choice which may identify vegetations or abscess formation around the valves.

Once a diagnosis of infective endocarditis is made, specialist endocarditis teams are usually involved in the ongoing management of the patient. Typically these comprise a microbiologist, cardiologist and a specialist in infectious diseases. Treatment is by high dose antibiotics and treatment may have to be extremely prolonged. Cardiac surgery is the treatment of last resort, and is often associated with a poor prognosis, especially in patients who have already been significantly debilitated by a period of critical illness. Despite optimum care, the mortality of patients who develop multi-system failure from acute endocarditis remains high.

This is a rapidly spreading soft-tissue infection, which can affect any part of the body. It frequently follows minor trauma, but the aetiology is not fully understood. Typically, the affected area is indurate and discoloured. Laboratory findings and other diagnostic tests may be useful, but the diagnosis is primarily clinical.

Multiple organisms have been implicated. Commonly it is caused by a synergistic infection with a mixture of Gram-negative and anaerobic organisms (e.g. Bacteroides species, Clostridium species and anaerobic streptococci) or by infection with group A streptococcus alone. Infection spreads along fascial planes, causing necrosis of skin and subcutaneous tissues. Muscle layers are usually spared. The infection may spread rapidly and can be fatal within a few hours. Treatment is by urgent and extensive surgical excision of infected and necrotic tissue together with appropriate antibiotics. Seek microbiological advice. (See Empirical antibiotic therapy, p. 336.)

Neisseria meningitidis is a Gram-negative organism, which approximately 10% of the population carry as a nasal commensal. It causes a spectrum of illness from meningitis (without systemic sepsis) to severe septicaemia resulting in multiple organ failure, limb loss and death within a few hours.

Although meningococcal sepsis is more common in paediatric intensive care, occasional cases occur in young adults. It can be a devastating illness resulting in death within a few hours. Always seek senior help.

Diagnosis

Early symptoms of systemic infection include fever (often >40°C), arthralgia, myalgia, headache and vomiting. The diagnosis of meningococcal sepsis is made on the basis of the typical non-blanching purpuric rash together with evidence of hypotension, tachycardia and poor perfusion.

The diagnosis of meningococcal sepsis is based on clinical signs. Life-saving antibiotic treatment (cefotaxime or benzylpenicillin) and resuscitation should be commenced immediately on suspicion. This must not be delayed by investigations.

Management

Antibiotics should be given as soon as the diagnosis is suspected.

Give high-flow oxygen by face mask. May require intubation and ventilation. Beware of cardiovascular collapse!

Establish i.v. access. Give fluids, crystalloid / colloid, to support the circulation. Large volumes are usually required to maintain blood pressure and improve peripheral circulation.

Establish invasive arterial blood pressure and haemodynamic monitoring CVP / pulmonary artery catheter or alternative.

Commence inotropes as required. Typically adrenaline (epinephrine) is first-line.

Peripheral and digital ischaemia. If blood pressure is adequate consider epoprostenol (prostacyclin) infusion 5–10 ng kg⁻¹ min⁻¹. This improves microvascular perfusion and may reduce risks of digital ischaemia.

Coagulopathy and DIC are common. Send coagulation screen. Avoid giving FFP, platelets and cryoprecipitate unless there is active bleeding as these may increase the tendency to microvascular thrombosis and worsen digital ischaemia.

Hypocalcaemia is common. Consider calcium bolus and possible calcium infusion.

Metabolic acidosis is normal. This will improve as the patient’s condition improves. Do not give bicarbonate unless extreme (pH < 7.1) or inotropes ineffective.

There is no evidence for the routine use of steroids in meningococcal shock but if adrenal insufficiency is suspected then replacement steroid therapy is appropriate. (This is in contrast to meningococcal meningitis in which recent evidence suggests that steroids may be of benefit. See Meningitis, p. 295.) Waterhouse–Friderichsen syndrome (adrenal haemorrhage / infarction) is rare and is usually a post-mortem finding.

Activated protein C may have a specific beneficial role in meningococcal sepsis in reducing the microvascular thrombosis and tissue ischaemia but numbers in adults are insufficient to prove benefit and studies in children have not shown benefit. (See Activated protein C, p. 333.)

There is increasing use of haemofiltration and plasma exchange in meningococcal sepsis to remove endotoxin, cytokines and other factors, in an attempt to improve overall survival and also to reduce the incidence of sequelae such as digital ischaemia. The benefits of these treatments are as yet not proven. You should seek senior advice.

Microbiological diagnosis

Although treatment is based on clinical suspicion, it is helpful to attempt to establish a microbiological diagnosis. Blood should be sent for culture and polymerase chain reaction (PCR). Skin lesions should be scraped onto a glass slide for microscopy and sent for culture. Seek microbiological advice.

Antibiotics

Meningococcus is usually sensitive to benzylpenicillin in the UK; however, other severe infections, most notably pneumococcal sepsis, may occasionally produce a similar clinical picture and purpuric rash, so high-dose cefotaxime is the first-line agent of choice. When meningococcal disease is confirmed later and the sensitivities are known, benzylpenicillin may be substituted. Neither of these antibiotics eradicates nasal carriage of meningococcus, and the patient should receive rifampicin or ciprofloxacin for this purpose during the recovery phase. (See Prophylaxis below.)

Prophylaxis

Most cases of meningococcal disease are sporadic and ‘outbreaks’ of infection are rare. However, the index patient, direct family contacts and other close contacts require prophylactic treatment with rifampicin (or ciprofloxacin) to abolish nasal carriage of meningococcus. This is organized by the public health department and the case should be reported to them as soon as possible. (See Notifiable infectious diseases below.)

It is not normally considered necessary for the medical or nursing staff involved in the care of these patients to receive prophylaxis, unless direct contamination has occurred.

In the UK there is a statutory duty to report a number of infectious diseases to the public health services. This is either to enable disease surveillance or because of the broad risk posed to contacts or the public generally. Notifiable infectious diseases are shown in Box 13.3.