oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Synonyms: septicaemia, blood poisoning
Arrange immediate admission to hospital for investigation and treatment.
Sepsis: the total body inflammatory response that occurs with severe infection.
Bacteraemia: presence of bacteria in the blood - eg, 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 (eg, 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 to raise awareness of severe sepsis and to improve its management. The SSC is a collaboration between several groups worldwide and its aim is to reduce the mortality from sepsis.
The SSC identifies a number of criteria for the diagnosis of sepsis (Table 1).
Criteria for the diagnosis of sepsis
Infection, documented or suspected and some of the following:
- General variables.
- Fever (>38.3°C).
- Hypothermia (core temperature <36°C).
- Heart rate >90 bpm - one or more than two SD above the normal value for age.
- Altered mental status.
- Significant oedema or positive fluid balance (>20 mL/kg over 24 hours).
- Hyperglycaemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes.
- Leukocytosis (WBC count >12,000 µL–1).
- Inflammatory variables.
- Leukopenia (WBC count < 4000 µL–1).
- Normal WBC count with greater than 10% immature forms.
- Plasma CRP more than two SD above the normal value.
- Plasma pro-calcitonin more than two SD above the normal value.
- Haemodynamic variables:
- Arterial hypotension (SBP <90 mm Hg, mean arterial pressure (MAP) <70 mm Hg, or an SBP decrease >40 mm Hg in adults or less than two SD below normal for age).
- Organ dysfunction variables.
- Arterial hypoxaemia (PaO2/FiO2 <300 mm Hg).
- Acute oliguria (urine output <0.5 mL/kg/hour for at least two hours despite adequate fluid resuscitation).
- Creatinine increase >0.5 mg/dL or 44.2 µmol/L.
- Coagulation abnormalities (INR >1.5 or activated partial thromboplastin time (aPTT) >60 seconds).
- Ileus (absent bowel sounds).
- Thrombocytopenia (platelet count <100,000 µL–1).
- Hyperbilirubinaemia (plasma total bilirubin >4 mg/dL or 70 µmol/L).
- Tissue perfusion variables:
- Hyperlactataemia (>1 mmol/L).
- Decreased capillary refill or mottling.
The SSC has also identified criteria for the diagnosis of severe sepsis (Table 2).
Identification of severe sepsis
Severe sepsis definition = sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following thought to be due to the infection)
- Sepsis-induced hypotension.
- Lactate above upper limits of laboratory normal.
- Urine output <0.5 mL/kg/hour for more than two hours despite adequate fluid resuscitation.
- Acute lung injury with PaO2/FiO2 <250 mm Hg in the absence of pneumonia as infection source.
- Acute lung injury with PaO2/FiO2 <200 mm Hg in the presence of pneumonia as infection source.
- Creatinine >2.0 mg/dL (176.8 µmol/L).
- Bilirubin >2 mg/dL (34.2 µmol/L).
- Platelet count <100,000 µL.
- Coagulopathy (INR >1.5).
Pathophysiology of sepsis
Sepsis involves a number of derangements; the following are a few:
- Abnormal coagulation.
- Endothelial cell dysfunction.
- Presence of excessive tumour necrosis factor.
- Cell apoptosis - eg, lymphocytes and endothelial cells.
- Neutrophil hyperactivity.
- Poor glycaemic control.
- Lack of steroid hormones.
- Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides and cell stress markers play key roles in sepsis pathophysiology.
- Current research is focusing on such issues as the immunosuppressive phase of host immune responses, mitochondrial dysfunction and the individual reactions between pathogen and the host immune system.
A study of the incidence and mortality of severe sepsis in England, Wales and Northern Ireland between 1993-2004 showed that 92,672 admissions (27.0%) had sepsis in the first 24 hours following admission. The percentage of admissions with severe sepsis during the first 24 hours rose from 23.5% in 1996 to 28.7% in 2004. Hospital mortality for admissions with severe sepsis decreased from 48.3% in 1996 to 44.7% in 2004 but the total number of deaths increased from an estimated 9,000 to 14,000. The treated incidence of severe sepsis per 100,000 population rose from 46 in 1996 to 66 in 2003, with the associated number of hospital deaths per 100,000 population rising from 23 to 30. It is the most common cause of death among critically ill patients in non-coronary intensive care units.
Lack of reliable epidemiological data makes global estimates difficult. However, it has been deduced that more than 1 in 1,000 people in developed countries develop sepsis each year and between a third and a half of them progress to severe sepsis. The figures for developing countries are likely to be far higher.
There is usually an abscess or nidus of infection, which may be occult. Risk factors for developing sepsis include the following:
- Age - the elderly and very young are at risk.
- Instrumentation or surgery (including illegal abortion occurring in unhygienic circumstances).
- Ethanol abuse.
- Diabetes mellitus.
- Medications - eg, high-dose corticosteroids, chemotherapy.
- Males are more prone than females to develop severe sepsis, although the mortality in females is higher. The reasons for this are not known.
- Black race.
- 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 - eg, lethargy, nausea and vomiting, abdominal pain and diarrhoea.
- Also enquire about symptoms relating to a possible focus of infection - eg, cough, recent travel.
- Looks unwell.
- Fever (may be 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).
- Drowsiness or impaired consciousness (common in the elderly but a late sign in young children and young adults).
- Features relating to actual infection - eg, rash in meningococcal sepsis, dullness to percussion in pneumonia.
These features may not be present in the very young, elderly and immunocompromised.
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.
- LFTs - hypoalbuminaemia likely to be present.
- Glucose - hyperglycaemia can be present.
- Clotting screen, including D-dimer and fibrinogen testing, looking for disseminated intravascular coagulation.
- Blood cultures - at least two 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.
- Disseminated intravascular coagulation.
- Adrenal failure - eg, adrenal haemorrhage secondary to meningococcus (Waterhouse-Friderichsen syndrome).
- Multiorgan failure - eg, renal failure or cardiorespiratory failure.
- Resuscitation - patients may require intubation and ventilation.
- Intravenous rehydration - aggressively if the patient is shocked.
- 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.
- Intravenous hydrocortisone - no longer used routinely and best avoided in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore haemodynamic stability. May be of use in children with absolute adrenal insufficiency..
- Intravenous antimicrobials - the choice should include broad-spectrum antibiotics given intravenously. Antivirals and antifungals may also be required, depending on clinical circumstances (eg, in immunocompromised patients). Once an organism is isolated then this regimen can be tailored for the patient. Empirical combination therapy should not be administered for more than 3-5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known
- Vasopressin may be required to combat hypotension with the addition of an inotrope such as dobutamine if cardiac dysfunction occurs.
- Statins have been shown to have anti-inflammatory, antioxidant, immunomodulatory and anti-apoptotic effects (= pleiotropic) and have emerged as potentially useful agents in various critical care areas such as bacteraemia, the early phases of sepsis and septic shock..
- Surgery may also be required - eg, wound debridement, abscess drainage.
Surviving Sepsis Campaign, early goal-directed therapy and 'bundles'
- The 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 Management bundle referred to in the 2008 guidance has been dispensed with, and the Resuscitation bundle has been split into two - interventions to be completed within three hours and those to be completed within six hours (Table 3).
- The focus of early goal-directed therapy (EGDT) has shifted to events in the first six hours of care. Early diagnosis, risk stratification using lactate levels, haemodynamic response after a fluid challenge, antibiotics, source control and haemodynamic optimisation are the mainstays of effective management.
The SSC therapy bundles
To be completed within three hours:
- Measure lactate level.
- Obtain blood cultures prior to administration of antibiotics.
- Administer broad-spectrum antibiotics.
- Administer 30 mL/kg crystalloid for hypotension or lactate 4 mmol/L.
To be completed within six hours:
- Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain an MAP ≥65 mm Hg.
- In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/L (36 mg/dL):
- Measure central venous pressure (CVP)*.
- Measure central venous oxygen saturation (ScvO2)*.
- Re-measure lactate if initial lactate was elevated*.
*Targets for quantitative resuscitation included in the guidelines are: CVP of ≥8 mm Hg, ScvO2 of 70% and normalisation of lactate.
Reproduced with permission. Copyright 2014 Society of Critical Care Medicine.
Initially, when these guidelines were published there were concerns that the evidence on which they were founded was limited and some suspected there was too much involvement of the pharmaceutical industry. However, despite these concerns, outcomes of the sepsis programmes are very good and, on average, a 10-20% reduction in overall mortality has been reported. In addition to this, length of hospital stay is reduced, resulting in this method being cost-effective. A decade after EGDT was introduced, studies have consistently shown that use of the resource bundle modulates inflammation, decreases organ failure progression and conserves healthcare resource consumption.
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). There is also evidence that sepsis can have a longer-term effect, worsening the outcome of patients who have chronic diseases. These figures can be improved with early goal-directed therapy. It has been estimated that this approach saves 1 in 6 lives for patients presenting with severe sepsis and septic shock.
Unsurprisingly, prognosis is worse in the elderly. A large American study of long-term mortality (90 days or more after admission) reported an overall mortality of 55% and 1- and 2-year mortality rates were 31% and 43%, respectively. Factors significantly associated with long-term mortality included congestive heart failure, peripheral vascular disease, dementia, diabetes with complications and use of mechanical ventilation. Smoking cessation and cardiac medications were associated with decreased long-term mortality rates.
Further reading & references
- Singer M; The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014 Jan 1;5(1):66-72. doi: 10.4161/viru.26907. Epub 2013 Nov 1.
- Wiersinga WJ, Leopold SJ, Cranendonk DR, et al; Host innate immune responses to sepsis. Virulence. 2014 Jan 1;5(1):36-44. doi: 10.4161/viru.25436. Epub 2013 Jun 17.
- Schlichting D, McCollam JS; Recognizing and managing severe sepsis: a common and deadly threat. South Med J. 2007 Jun;100(6):594-600.
- International guidelines for management of severe sepsis and septic shock; Surviving Sepsis Campaign, 2012
- Remick DG; Pathophysiology of sepsis. Am J Pathol. 2007 May;170(5):1435-44.
- Skibsted S, Jones AE, Puskarich MA, et al; Biomarkers of endothelial cell activation in early sepsis. Shock. 2013 May;39(5):427-32. doi: 10.1097/SHK.0b013e3182903f0d.
- Aziz M, Jacob A, Yang WL, et al; Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013 Mar;93(3):329-42. doi: 10.1189/jlb.0912437. Epub 2012 Nov 7.
- Opal SM; The current understanding of sepsis and research priorities for the future. Virulence. 2014 Jan 1;5(1):1-3. doi: 10.4161/viru.26803. Epub 2013 Oct 23.
- Harrison DA, Welch CA, Eddleston JM; The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care. 2006;10(2):R42.
- Mayr FB, Yende S, Angus DC; Epidemiology of severe sepsis. Virulence. 2014 Jan 1;5(1):4-11. doi: 10.4161/viru.27372. Epub 2013 Dec 11.
- Jawad I, Luksic I, Rafnsson SB; Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012 Jun;2(1):010404. doi: 10.7189/jogh.02.010404.
- Guidet B, Maury E; Sex and severe sepsis. Crit Care. 2013 May 15;17(3):144.
- Karnatovskaia LV, Festic E; Sepsis: a review for the neurohospitalist. Neurohospitalist. 2012 Oct;2(4):144-53. doi: 10.1177/1941874412453338.
- McLelland M et al; Early identification and treatment of sepsis, Nursing Times, 2014.
- Kouroumichakis I, Papanas N, Proikaki S, et al; Statins in prevention and treatment of severe sepsis and septic shock. Eur J Intern Med. 2011 Apr;22(2):125-33. doi: 10.1016/j.ejim.2010.12.004. Epub 2011 Jan 5.
- Rivers EP, Katranji M, Jaehne KA, et al; Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol. 2012 Jun;78(6):712-24. Epub 2012 Mar 23.
- 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.
- 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.
- 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.
- 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.
- Lemay AC, Anzueto A, Restrepo MI, et al; Predictors of long-term mortality after severe sepsis in the elderly. Am J Med Sci. 2014 Apr;347(4):282-8. doi: 10.1097/MAJ.0b013e318295a147.
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Dr Gurvinder Rull
Dr Laurence Knott
Dr Hayley Willacy