Synonyms: sepsis, blood poisoning

Definitions

Bacteraemia - presence of bacteria in the blood, e.g. following dental procedures. If there is only a trivial amount then it is usually handled by a competent immune system with no systemic effects. However, if the patient has damaged heart valves they are at risk of infective endocarditis.

A greater amount of bacteria can cause systemic signs and symptoms with a number of sequelae. For example, spontaneous resolution, development of focal infection, e.g. pneumonia or abscess formation with or without sepsis, or sepsis with no obvious focal infection.

Septicaemia - there is presence of numerous bacteria in the blood, which are actively dividing. This results in a systemic response leading to organ dysfunction.
Septicaemia is a serious illness and often fatal. It can be complicated by circulatory collapse, myocardial depression, increased metabolic rate and vasoregulatory perfusion abnormalities. Thus it must not be viewed as simply being an infection alone.

The Surviving Sepsis Campaign (SSC) was established in the last decade to raise awareness of severe sepsis and to improve its management.¹ The Surviving Sepsis Campaign is a collaboration between several groups worldwide and its aim is to reduce the mortality from sepsis.

The SSC defines sepsis as a disease continuum with 3 groups:

• Systemic inflammatory response syndrome (SIRS):
  In adults this is a clinical response arising from a nonspecific insult, including 2 or more of the following:
  • Temperature (>38°C or <36°C).
  • Heart rate >90 beats per minute (bpm).
  • Respiratory rate >20 per minute or PCO₂ <32 mm Hg.
  • White cell count greater than 12 x 10⁹ cells/L or less than 4 x 10⁹ cells/L or >10% immature neutrophils.
• Sepsis: SIRS as above with presumed or confirmed infectious process.
• Severe sepsis: sepsis with one or more signs of organ dysfunction, hypoperfusion or hypotension (e.g. septic shock or respiratory failure).

Pathophysiology of sepsis²

Sepsis involves a number of derangements; the following are a few:

• Abnormal coagulation.
• Endothelial injury.
• Presence of excessive tumour necrosis factor.
• Cell apoptosis, e.g. lymphocytes and endothelial cells.
• Neutrophil hyperactivity.
• Poor glycaemic control.
• Lack of steroid hormones.

Epidemiology

The Surviving Sepsis Campaign (SSC) estimates that the incidence of sepsis is 3 per 1,000 worldwide. Thus the number of cases each year probably reaches 18 million and this, associated with its high mortality rate, makes it a leading cause of death.³

Risk factors

There is usually an abscess or nidus of infection, which may be occult. Risk factors for developing sepsis include the following:

• Age - elderly and very young at risk.
• Instrumentation or surgery (including illegal abortion occurring in unhygienic circumstances).
• Ethanol abuse.
• Diabetes mellitus.
• Burns.
• Immunocompromise.
• Medications, e.g. high dose corticosteroids, chemotherapy.

Presentation

• Patients may present a few days earlier with a focus of infection.
• Patients may then deteriorate rapidly despite having the appropriate oral antibiotics.
• Nonspecific symptoms are common, e.g. lethargy, nausea and vomiting, abdominal pain and diarrhoea.
• Also inquire about symptoms relating to a possible focus of infection, e.g. cough, recent travel.

Clinical features

• Looks unwell.
• Fever (maybe spiking) and/or rigors.
• Tachycardia, tachypnoea and cyanosis.
• Hyperdynamic circulation with a bounding pulse (early on).
• Poor capillary refill and cold peripheries occur later.
• Hypotension with a postural drop (indicates septic shock).
• Sweating.
• Lymphadenopathy.
• Hepatosplenomegaly.
• Drowsiness or impaired consciousness (common in the elderly but a late sign in young children and young adults).
• Features relating to actual infection, e.g. rash in meningococcal sepsis, dullness to percussion in pneumonia.

These features may not be present in the very young, elderly and immunocompromised.

Investigations

Remember - septicaemia is a clinical diagnosis.

Investigations should include:

• FBC - anaemia, neutrophilia or neutropenia, thrombocytopenia may be present (pancytopenia may indicate bone marrow involvement). In viral infections lymphocytosis predominates.
• Urine dipstick and sample for microscopy, culture and sensitivity.
• Renal function - looking at extent of dehydration or organ failure.
• Liver function tests - hypoalbuminaemia likely to be present.
• Glucose - hyperglycaemia can be present.
• Clotting screen, including D-dimer and fibrinogen testing, looking for disseminated intravascular coagulation (DIC).
• Blood cultures - several sets from several sites are required. Cultures for mycobacteria should also be sent. Ideally these should be sent before antibiotics are given - but do not delay, especially if the patient is very ill.
• Radiology - including CXR, abdominal ultrasound looking for a collection, and CT scan looking for source.
• Measures of lactate and oxygen saturation of venous blood (SvO₂ - see below).
• Arterial blood gases - metabolic acidosis is common.
• More invasive investigations looking for a source of infection - for example, lumbar puncture, bronchoscopy, laparoscopy, lymph node biopsy, etc.

Complications

• Disseminated intravascular coagulation (DIC).
• Adrenal failure, e.g. adrenal haemorrhage secondary to meningococcus (Waterhouse-Friderichsen syndrome),
• Multiorgan failure, e.g. renal failure or cardiorespiratory failure.

Management

Supportive care

• Resuscitation - patients may require intubation and ventilation.
• Intravenous rehydration - aggressively if the patient is shocked.
• Intravenous hydrocortisone - patients may have adrenal dysfunction (consider especially if they have refractory hypotension).
• Monitoring the patient - this may require measures of central venous pressure (CVP) and urinary output with a catheter.
• Intravenous insulin may be required until the septicaemia resolves.

Specific therapy

• Intravenous antibiotics - the choice should include broad-spectrum antibiotics given intravenously. Once an organism is isolated then this regimen can be tailored for the patient.
• Immunocompromised patients may have unusual organisms including fungi - thus, help of microbiologist and virologist may be required.
• Surgery may also be required, e.g. wound debridement, abscess drainage.

Surviving Sepsis Campaign, early goal-directed therapy and 'bundles'

• The Surviving Sepsis Campaign (SSC) was established to raise awareness of severe sepsis and to improve its management. It is a collaboration between the Society of Critical Care Medicine (SCCM), the European Society of Intensive Care Medicine (ESICM) and the International Sepsis Forum (ISF).
• The campaign has devised guidelines which are divided into 'bundles'. Bundles represent groups of evidence-based recommendations within a single protocol. The idea is that following these bundles improves patient survival.
• The guidelines highlight that early aggressive management of sepsis, i.e. before the patient ends up in an intensive care setting, is crucial for improving patient outcomes.⁴

Some of the recommendations include the following³

• Aggressive rehydration titrated to a central venous pressure (CVP) of 8-12 mm Hg - using high volumes of crystalloids.
• Earlier use of blood transfusion, e.g. haemoglobin level <10 g/dL provided the patient resuscitated to CVP 8-12 mm Hg.
• Using SvO₂ to determine oxygenation of tissues. SvO₂ is an estimate of oxygen saturation of blood returning to the right side of the heart. SvO₂ <65% is associated with a worse prognosis and, provided CVP, haemoglobin and mean arterial pressure are satisfactory, patients should be started on a dobutamine.
• Early and appropriate empirical antibiotic therapy.

Drotrecogin alfa (activated) for severe sepsis⁹

Drotrecogin alfa (activated) is a recombinant form of human activated protein C (APC). APC enhances fibrinolysis, prevents thrombosis and has anti-inflammatory properties. In sepsis, APC levels are reduced and there is also an inability to produce APC. It is given as an intravenous infusion and its main adverse effect is bleeding. Thus, it is not for use in patients who are actively bleeding, who have severe hepatic disease or intracranial pathology. See Summary of Product for full details.¹⁰ The recombinant human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, a phase III study, was cut short as it was discovered that significant reductions in mortality were occurring in patients with severe sepsis receiving drotrecogin alfa.¹¹

Prognosis

Sepsis, especially when there is a delay in institution of therapy, is associated with 40% mortality (which increases to over 60% in the presence of septic shock).³ These figures can be improved with early goal-directed therapy.

Document references

1. Schlichting D, McCollam JS; Recognizing and managing severe sepsis: a common and deadly threat. South Med J. 2007 Jun;100(6):594-600. [abstract]
2. Remick DG; Pathophysiology of sepsis. Am J Pathol. 2007 May;170(5):1435-44. [abstract]
3. Otero RM, Nguyen HB, Huang DT, et al; Early goal-directed therapy in severe sepsis and septic shock revisited: concepts, controversies, and contemporary findings. Chest. 2006 Nov;130(5):1579-95. [abstract]
4. Rivers E, Nguyen B, Havstad S, et al; Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. [abstract]
5. Patel GP, Elpern EH, Balk RA; A campaign worth joining: improving outcome in severe sepsis and septic shock using the Surviving Sepsis Campaign guidelines. South Med J. 2007 Jun;100(6):557-8.
6. Eichacker PQ, Natanson C, Danner RL; Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med. 2006 Oct 19;355(16):1640-2.
7. Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, et al; Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and Crit Care Med. 2010 Apr;38(4):1036-43. [abstract]
8. Levy MM, Dellinger RP, Townsend SR, et al; The Surviving Sepsis Campaign: results of an international guideline-based Intensive Care Med. 2010 Feb;36(2):222-31. Epub 2010 Jan 13. [abstract]
9. Sepsis (severe) - drotrecogin, NICE (2004)
10. Summary of Product Characteristics (SPC) - Xigris® powder for solution for infusion, (Drotrecogin Alfa), Eli Lilly and Company Ld, July 2007
11. Bernard GR, Vincent JL, Laterre PF, et al; Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. [abstract]

Internet and further reading

• International guidelines for management of severe sepsis and septic shock, Surviving Sepsis Campaign (2008)

Acknowledgements