- Email: [email protected]
Sepsis: older and newer concepts
Viewpoint
Sepsis: older and newer concepts Jean-Louis Vincent, Jean-Paul Mira, Massimo Antonelli
Sepsis is a common complication in patients in intensive care units and a frequent reason for intensive care unit admission. Sepsis is a major cause of morbidity and mortality and, without specific antisepsis therapies, management relies on infection control and organ support. For these interventions to be most effective, they must be started early, which highlights the need for all health-care workers to be aware of sepsis so that diagnosis can be made as early as possible. In this Viewpoint, we discuss some of the earlier terms used to characterise and define sepsis, and point out some of their limitations. We then introduce some aspects of new consensus definitions, proposed by an expert panel, which highlight in particular the importance of organ dysfunction. These definitions should help provide a more standardised approach to the identification of patients with suspected sepsis in both clinical practice and clinical research.
Introduction Sepsis is hard to define. The word sepsis has been around for centuries, and was used as early as the time of the ancient Greeks (σηψLς) to describe decomposition or putrefaction.1 The term thus existed long before anything was known about the microorganisms and immunological responses responsible for this often lethal condition. Although the clinical picture of sepsis has not changed much since those early days, our ability to support failing organs has altered how we manage sepsis, such that individuals can now survive severe infections that would previously have been fatal. With these advances in organ support, many aspects of the immunological response have been unravelled, and our understanding of the basic pathogenesis and pathophysiology of sepsis has improved. Along with these changes, the realisation of the importance of early diagnosis and management, and the need to identify appropriate patient groups for clinical research,2 has come a need to define sepsis more precisely.
Older concepts A North American consensus definitions conference held in 19913 caused considerable controversy when the participants attempted to simplify the concept by proposing that sepsis represented the association between infection and signs of the systemic inflammatory response syndrome. The presence of infection is certainly essential for a diagnosis of sepsis. Some patients might have a sepsis-like state without evidence of an infection4—a good example is a patient who develops a hyperkinetic state after cardiac surgery without any infection—but the prognostic and therapeutic implications of this condition are very different from those of true sepsis. The notion of inflammation, however, carries little meaning, because inflammation is a very non-specific response to any insult, from minor trauma to complicated autoimmune disease. Moreover, sepsis is now well established as more than just a proinflammatory response, and includes a complex interplay of proinflammatory and anti-inflammatory responses. The systemic inflammatory response syndrome criteria are even less appropriate than just considering inflammation for two main reasons.5 First, they are too sensitive, as any form of stress can result in
tachycardia, hyperventilation, and even leucocytosis, although, in some cases, the systemic inflammatory response syndrome criteria might not be sensitive enough.6 Second, the systemic inflammatory response syndrome primarily includes signs of infection (eg, fever and increased white blood cell count); therefore, by this definition, sepsis is effectively synonymous with infection. Yet, although all patients with sepsis do undoubtedly have an infection, even if we are not always able to clearly identify it, not all infected patients have sepsis. Some researchers and clinicians believe that the incidence of sepsis is increasing. However, this idea has been promoted, in part, to attract attention to the global problem of sepsis, which is largely neglected by political and financing authorities. Many researchers have restricted their epidemiological considerations to infectious disease, thinking only in terms of antibiotic use, and confining sepsis prevention to hygiene and vaccines. But sepsis is so much more complex than this simplistic approach allows for. Clinicians worldwide have been encouraged to diagnose sepsis, even by way of financial incentives via increased reimbursement rates. If sepsis is defined simply as infection, as is effectively the case with the systemic inflammatory response syndrome definition, then the number of cases of sepsis has certainly increased considerably and the mortality rates for these less severely ill patients have simultaneously decreased.7 These observations are primarily an artifact of reporting.8 The true incidence of sepsis and its associated mortality are difficult to state with any precision. Aside from problems of definition, our epidemiological data are largely restricted to the intensive care unit (ICU) population, in which mortality rates are close to 30–35%;9 but many patients with sepsis are not admitted to the ICU, for example, patients with terminal cancer or end-stage cirrhosis or simply very elderly people who develop infection at the end of their life (William Osler referred to pneumonia, a common cause of sepsis, as the “friend of the aged”).10
Lancet Respir Med 2016 Published Online February 22, 2016 http://dx.doi.org/10.1016/ S2213-2600(15)00522-6 Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium (Prof J-L Vincent MD); Medical Intensive Care Unit, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique des Hôpitaux de Paris, Paris, France (Prof J-P Mira MD); and Department of Intensive Care and Anesthesiology, Università Cattolica del Sacro Cuore, Rome, Italy (Prof M Antonelli MD) Correspondence to: Prof Jean-Louis Vincent, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium [email protected]
Newer concepts In 2001, an attempt was made to revisit the systemic inflammatory response syndrome criteria,11 but the resultant list of signs and symptoms of sepsis was too
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
1
Viewpoint
1
2
3
4
Respiration, PaO2/FiO2 mm Hg
>400
0
≤400
≤300
≤200 (with respiratory support)
≤100 (with respiratory support)
Coagulation, platelets × 103/mm3
>150
≤150
≤100
≤50
≤20
Liver, bilirubin mg/dL (μmol/L)
<1·2 (<20)
1·2–1·9 (20–32)
2·0–5·9 (33–101)
6·0–11·9 (102–204)
>12·0 (>204)
Cardiovascular, hypotension
No hypotension
MAP <70 mm Hg
Dopamine ≤5 μg/kg per min or dobutamine (any dose)*
Dopamine >5 μg/kg per min or epinephrine ≤0·1 μg/kg per min or norepinephrine ≤0·1* μg/kg per min
Dopamine >15 μg/kg per min or epinephrine >0·1 μg/kg per min or norepinephrine >0·1* μg/kg per min
Central nervous system, Glasgow Coma Scale score
15
13–14
10–12
6–9
<6
Renal, creatinine mg/dL (μmol/L)
<1·2 (<110)
1·2–1·9 (110–170)
2·0–3·4 (171–299)
3·5–4·9 (300–440)
>5·0 (>440)
Renal, urine output mL per day
..
..
..
<500
<200
PaO2/FiO2=ratio of arterial oxygen partial pressure to fractional inspired oxygen. MAP=mean arterial pressure. *Adrenergic agents administered for at least 1 h.
Table 1: The sequential organ failure assessment (SOFA) score12
Altered tissue perfusion, elevated serum lactate concentration, need for vasopressors
Septic shock
Sepsis
Organ dysfunction Fever, altered white blood cell count
Infection Colonisation
Severity
Figure 1: Different severities of sepsis and associated changes in clinical signs
Clinical scenario
Fever, Possible White blood cell tachycardia source count, C-reactive protein, procalcitonin
Organ dysfunction Fever, tachycardia
Bacteriology
Possible source Infection
If associated with infection
If associated with organ dysfunction Sepsis
White blood cell count, C-reactive protein, procalcitonin Bacteriology
Sepsis
Figure 2: Importance of unexplained organ dysfunction in the diagnosis of sepsis In clinical situations, sepsis is more frequently identified by the presence of unexplained organ dysfunction than by the presence of infection.
long to be widely accepted, and the systemic inflammatory response syndrome criteria, however inadequate, continued to be used. In 2014, the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine put together a group of experts (including J-LV, one of the coauthors of this Viewpoint) from different scientific and clinical backgrounds to create a consensus update on sepsis definitions that could be adopted worldwide for clinical and research use. We would argue that these so-called new definitions are not 2
actually new, but rather a return to the real roots of sepsis. If a clinician is asked to describe the last case of sepsis they encountered, the answer will almost certainly include words such as hypotension, respiratory distress, oliguria, coagulopathy, and altered mental status. These terms indicate dysfunction of various organ systems, which can be assessed using organ dysfunction scores, of which the sequential organ failure assessment (SOFA) score12 (table 1) is one of the most widely used and validated. The consensus group proposes that sepsis be regarded as the presence of life-threatening organ dysfunction, quantified by an increase in the SOFA subscore of at least 2 for the organ in question, which occurs as the result of a dysregulated host response to an infection,13 a suggestion that has gained general acceptance in recent years.4 Septic shock, the most severe form of sepsis (figure 1), is a form of acute circulatory failure due to sepsis. Septic shock is clinically identified by the presence of hypotension that necessitates vasopressor therapy, and is associated with signs of altered tissue perfusion, such as altered skin perfusion, decreased urine output, and altered mental status. The diagnosis of shock is confirmed by elevated blood lactate levels (greater than 2 mmol/L). Changes in organ function can, of course, be caused by factors other than sepsis, but separation of what is due to sepsis itself and what is due to other elements is difficult. As noted earlier, the presence of infection is not always obvious, so in the clinical situation, it is not always possible to identify sepsis by looking for organ dysfunction in a patient with known infection. More often, the opposite approach is more applicable, with physicians asking whether the new onset of unexplained hypoxaemia, oliguria, thrombocytopenia, or altered mental status suggests that their patient has sepsis—ie, the presence of unexplained, new-onset organ dysfunction should prompt a search for infection (figure 2).
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
Viewpoint
Clinical
Laboratory or treatment-related
Predisposing factors
Age, immunosuppression, comorbidities, alcoholism, drugs, etc
Genetic factors, cellular markers (eg, HLA-DR)
Infection
Signs of pneumonia, meningitis, peritonitis, purpura, etc
Chest x-ray, CT scan, etc Microbiological results, bacterial DNA, endotoxin, etc
Response
Fever, tachycardia, tachypnoea, etc
WBC, CRP, PCT, other sepsis markers
Organ dysfunction
Shock, oliguria, respiratory failure, coagulopathy, etc
Lactate, creatinine, PaO2/FiO2, platelet count
HLA-DR=human leucocyte antigen DR. WBC=white blood cell count. CRP=C-reactive protein. PCT=procalcitonin. PaO2/FiO2=ratio of arterial oxygen partial pressure to fractional inspired oxygen.
Table 2: The predisposing factors, infection, response, organ dysfunction (PIRO) classification model11
Sepsis is clearly more than just an infection that can be identified by the affected organ (eg, pneumonia, urinary tract infection, meningitis) and the type of microorganism (eg, pneumococcal, meningococcal, Candida, herpes virus). Sepsis is a heterogeneous disorder, which can be associated with many different types of infection and several other characteristics. This heterogeneity is why the predisposing factors, infection, response, organ dysfunction (PIRO) classification system was introduced more than 10 years ago to try and provide a framework by which the different components of the complex disease process could be separately characterised (table 2).11 In this model, P represents predisposing factors, including genetics, past history, and clinical context; I includes aspects of the (confirmed or suspected) infectious source and the microorganism responsible (when this information is available); R refers to the patient’s response in terms of vital signs and sepsis markers, such as C-reactive protein, procalcitonin or human leucocyte antigen DR; and O represents the extent of organ dysfunction, based on the six organs whose function can be easily assessed. Another important aspect is to identify sepsis early. The SOFA score is well recognised as a valuable method to characterise organ dysfunction, but it is somewhat complex for early identification of the patient with sepsis outside an ICU setting. In the past year, analyses of large databases showed that three simple elements within the score can provide sufficient information to trigger an alarm signal: tachypnoea, hypotension, and altered mentation. These have been included in what is called a quick SOFA (qSOFA).13 This model has the advantage of being simple and easy to remember. Nurses and other health-care workers on the general floor, who are perhaps not so familiar with the signs of sepsis, might find it particularly useful. In a patient with suspected infection, the qSOFA could thus be used to suggest the need to call for a member of staff who is trained to deal with sepsis, or perhaps a designated sepsis team, to do a panel of laboratory tests (including blood lactate concentrations) to characterise organ dysfunction and to increase surveillance of the patient and arrange transfer to the ICU. Findings from several studies have shown the important role of nurses in detecting early alarm signals,14,15 largely because of their frequent presence at
the patient’s bedside. Importantly, the SOFA (and qSOFA) score reflects both chronic and acute alterations in organ function, so that changes in SOFA scores over time are more useful than a single static value.16 But do we actually need the term sepsis at all? Why can’t we simply refer to the disorder as severe infection? Although this is indeed debatable, we believe the term sepsis is important for two key reasons: first, it stresses the severity of the problem and the need for urgent and vigorous action. Contacting the ICU doctor for a septic patient produces a more urgent response than for a patient with a severe infection, and a rapid reaction is essential to improve outcomes in these life-threatening situations. Early haemodynamic resuscitation is crucial, together with rapid control of infection, which includes not only the prompt administration of broad-spectrum antibiotics to target all likely causative microorganisms, but also a thorough search for a source of infection. Whenever possible, clinicians should be source-specific when using the term sepsis and speak about urinary sepsis, sepsis secondary to pneumonia, and so on. In addition to providing useful management and prognostic information, this approach will encourage us not to be satisfied with a diagnosis of sepsis, but to continue to look for the source of infection. The second reason to keep the term sepsis is because it might help trigger use of a specific therapy to help the patient regain an appropriate host-response. Admittedly, no sepsis-specific therapies are currently available, but effective strategies will undoubtedly be developed in the near future; these strategies were reviewed in a Commission2 in 2015. New sepsis therapies will be more personalised and targeted at a specific pathophysiological alteration (eg, endothelial damage and oedema formation for selepressin), a relevant mediator (eg, coagulopathy for thrombomodulin, blood gelsolin levels for gelsolin administration), or specific organ function (eg, alkaline phosphatase for renal dysfunction, interferon β for lung dysfunction).
Conclusion So, is this new consensus a big step? Not really, but it is a welcome and necessary update. The systemic inflammatory response syndrome was a (long) hiccup in the history of sepsis, and we are now heading back towards a more representative and realistic definition.
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
3
Viewpoint
Search strategy and selection criteria We selected relevant literature published in English based largely on our personal knowledge of developments in sepsis research.
Just as monitoring alone cannot improve outcomes,17 altered definitions cannot be said to represent major progress in terms of patient management. Introduction of the new Berlin definitions of acute respiratory distress syndrome18 into an ICU is unlikely to improve the management of severe respiratory failure; similarly with the new definitions of acute kidney injury.19 Perhaps we spend too much time on definitions. Nevertheless, an update of sepsis terminology was long overdue and there was a real need for a usable working definition of sepsis to be established, both for clinical practice and clinical research use.2 This consensus has provided some clarity regarding this still too often fatal disease, such as the importance of the organ dysfunction component and the need for early recognition, which should help to provide a more standardised approach to the identification and management of the patient with suspected sepsis. Contributors J-LV wrote the first draft of the manuscript. J-PM and MA critically revised the text. All authors approved the final version.
5 6
7
8 9
10 11
12
13
14
15
16
Declaration of interests We declare no competing interests. References 1 Geroulanos S, Douka ET. Historical perspective of the word “sepsis”. Intensive Care Med 2006; 32: 2077. 2 Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015; 15: 581–614. 3 American College of Chest Physicians, Society of Critical Care Medicine. Consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864–74. 4 Vincent JL, Opal S, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet 2013; 381: 774–75.
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18 19
Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you… Crit Care Med 1997; 25: 372–74. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372: 1629–38. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 2014; 311: 1308–16. Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution. N Engl J Med 2014; 370: 1673–76. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med 2014; 2: 380–86. Osler W. Pneumonia. In: The principles and practice of medicine, 3rd edn. London: D Appleton and Company, 1898: 109. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250–56. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/ failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707–10. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; published online Feb 22. DOI:10.1001/ Jama.2016.0287. Gyang E, Shieh L, Forsey L, Maggio P. A nurse-driven screening tool for the early identification of sepsis in an intermediate care unit setting. J Hosp Med 2015; 10: 97–103. Douw G, Schoonhoven L, Holwerda T, et al. Nurses’ worry or concern and early recognition of deteriorating patients on general wards in acute care hospitals: a systematic review. Crit Care 2015; 19: 230. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001; 286: 1754–58. Vincent JL, Rhodes A, Perel A, et al. Clinical review: update on hemodynamic monitoring—a consensus of 16. Crit Care 2011; 15: 229. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Kidney Disease Improving Global Outcomes Acute Kidney Injury Work Group. Kidney Disease Improving Global Outcomes Clinical practice guideline for acute kidney injury. Section 2: AKI definition. Kidney Int Suppl 2012; 2: 19–36.
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
Sepsis: older and newer concepts Jean-Louis Vincent, Jean-Paul Mira, Massimo Antonelli
Sepsis is a common complication in patients in intensive care units and a frequent reason for intensive care unit admission. Sepsis is a major cause of morbidity and mortality and, without specific antisepsis therapies, management relies on infection control and organ support. For these interventions to be most effective, they must be started early, which highlights the need for all health-care workers to be aware of sepsis so that diagnosis can be made as early as possible. In this Viewpoint, we discuss some of the earlier terms used to characterise and define sepsis, and point out some of their limitations. We then introduce some aspects of new consensus definitions, proposed by an expert panel, which highlight in particular the importance of organ dysfunction. These definitions should help provide a more standardised approach to the identification of patients with suspected sepsis in both clinical practice and clinical research.
Introduction Sepsis is hard to define. The word sepsis has been around for centuries, and was used as early as the time of the ancient Greeks (σηψLς) to describe decomposition or putrefaction.1 The term thus existed long before anything was known about the microorganisms and immunological responses responsible for this often lethal condition. Although the clinical picture of sepsis has not changed much since those early days, our ability to support failing organs has altered how we manage sepsis, such that individuals can now survive severe infections that would previously have been fatal. With these advances in organ support, many aspects of the immunological response have been unravelled, and our understanding of the basic pathogenesis and pathophysiology of sepsis has improved. Along with these changes, the realisation of the importance of early diagnosis and management, and the need to identify appropriate patient groups for clinical research,2 has come a need to define sepsis more precisely.
Older concepts A North American consensus definitions conference held in 19913 caused considerable controversy when the participants attempted to simplify the concept by proposing that sepsis represented the association between infection and signs of the systemic inflammatory response syndrome. The presence of infection is certainly essential for a diagnosis of sepsis. Some patients might have a sepsis-like state without evidence of an infection4—a good example is a patient who develops a hyperkinetic state after cardiac surgery without any infection—but the prognostic and therapeutic implications of this condition are very different from those of true sepsis. The notion of inflammation, however, carries little meaning, because inflammation is a very non-specific response to any insult, from minor trauma to complicated autoimmune disease. Moreover, sepsis is now well established as more than just a proinflammatory response, and includes a complex interplay of proinflammatory and anti-inflammatory responses. The systemic inflammatory response syndrome criteria are even less appropriate than just considering inflammation for two main reasons.5 First, they are too sensitive, as any form of stress can result in
tachycardia, hyperventilation, and even leucocytosis, although, in some cases, the systemic inflammatory response syndrome criteria might not be sensitive enough.6 Second, the systemic inflammatory response syndrome primarily includes signs of infection (eg, fever and increased white blood cell count); therefore, by this definition, sepsis is effectively synonymous with infection. Yet, although all patients with sepsis do undoubtedly have an infection, even if we are not always able to clearly identify it, not all infected patients have sepsis. Some researchers and clinicians believe that the incidence of sepsis is increasing. However, this idea has been promoted, in part, to attract attention to the global problem of sepsis, which is largely neglected by political and financing authorities. Many researchers have restricted their epidemiological considerations to infectious disease, thinking only in terms of antibiotic use, and confining sepsis prevention to hygiene and vaccines. But sepsis is so much more complex than this simplistic approach allows for. Clinicians worldwide have been encouraged to diagnose sepsis, even by way of financial incentives via increased reimbursement rates. If sepsis is defined simply as infection, as is effectively the case with the systemic inflammatory response syndrome definition, then the number of cases of sepsis has certainly increased considerably and the mortality rates for these less severely ill patients have simultaneously decreased.7 These observations are primarily an artifact of reporting.8 The true incidence of sepsis and its associated mortality are difficult to state with any precision. Aside from problems of definition, our epidemiological data are largely restricted to the intensive care unit (ICU) population, in which mortality rates are close to 30–35%;9 but many patients with sepsis are not admitted to the ICU, for example, patients with terminal cancer or end-stage cirrhosis or simply very elderly people who develop infection at the end of their life (William Osler referred to pneumonia, a common cause of sepsis, as the “friend of the aged”).10
Lancet Respir Med 2016 Published Online February 22, 2016 http://dx.doi.org/10.1016/ S2213-2600(15)00522-6 Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium (Prof J-L Vincent MD); Medical Intensive Care Unit, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique des Hôpitaux de Paris, Paris, France (Prof J-P Mira MD); and Department of Intensive Care and Anesthesiology, Università Cattolica del Sacro Cuore, Rome, Italy (Prof M Antonelli MD) Correspondence to: Prof Jean-Louis Vincent, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium [email protected]
Newer concepts In 2001, an attempt was made to revisit the systemic inflammatory response syndrome criteria,11 but the resultant list of signs and symptoms of sepsis was too
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
1
Viewpoint
1
2
3
4
Respiration, PaO2/FiO2 mm Hg
>400
0
≤400
≤300
≤200 (with respiratory support)
≤100 (with respiratory support)
Coagulation, platelets × 103/mm3
>150
≤150
≤100
≤50
≤20
Liver, bilirubin mg/dL (μmol/L)
<1·2 (<20)
1·2–1·9 (20–32)
2·0–5·9 (33–101)
6·0–11·9 (102–204)
>12·0 (>204)
Cardiovascular, hypotension
No hypotension
MAP <70 mm Hg
Dopamine ≤5 μg/kg per min or dobutamine (any dose)*
Dopamine >5 μg/kg per min or epinephrine ≤0·1 μg/kg per min or norepinephrine ≤0·1* μg/kg per min
Dopamine >15 μg/kg per min or epinephrine >0·1 μg/kg per min or norepinephrine >0·1* μg/kg per min
Central nervous system, Glasgow Coma Scale score
15
13–14
10–12
6–9
<6
Renal, creatinine mg/dL (μmol/L)
<1·2 (<110)
1·2–1·9 (110–170)
2·0–3·4 (171–299)
3·5–4·9 (300–440)
>5·0 (>440)
Renal, urine output mL per day
..
..
..
<500
<200
PaO2/FiO2=ratio of arterial oxygen partial pressure to fractional inspired oxygen. MAP=mean arterial pressure. *Adrenergic agents administered for at least 1 h.
Table 1: The sequential organ failure assessment (SOFA) score12
Altered tissue perfusion, elevated serum lactate concentration, need for vasopressors
Septic shock
Sepsis
Organ dysfunction Fever, altered white blood cell count
Infection Colonisation
Severity
Figure 1: Different severities of sepsis and associated changes in clinical signs
Clinical scenario
Fever, Possible White blood cell tachycardia source count, C-reactive protein, procalcitonin
Organ dysfunction Fever, tachycardia
Bacteriology
Possible source Infection
If associated with infection
If associated with organ dysfunction Sepsis
White blood cell count, C-reactive protein, procalcitonin Bacteriology
Sepsis
Figure 2: Importance of unexplained organ dysfunction in the diagnosis of sepsis In clinical situations, sepsis is more frequently identified by the presence of unexplained organ dysfunction than by the presence of infection.
long to be widely accepted, and the systemic inflammatory response syndrome criteria, however inadequate, continued to be used. In 2014, the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine put together a group of experts (including J-LV, one of the coauthors of this Viewpoint) from different scientific and clinical backgrounds to create a consensus update on sepsis definitions that could be adopted worldwide for clinical and research use. We would argue that these so-called new definitions are not 2
actually new, but rather a return to the real roots of sepsis. If a clinician is asked to describe the last case of sepsis they encountered, the answer will almost certainly include words such as hypotension, respiratory distress, oliguria, coagulopathy, and altered mental status. These terms indicate dysfunction of various organ systems, which can be assessed using organ dysfunction scores, of which the sequential organ failure assessment (SOFA) score12 (table 1) is one of the most widely used and validated. The consensus group proposes that sepsis be regarded as the presence of life-threatening organ dysfunction, quantified by an increase in the SOFA subscore of at least 2 for the organ in question, which occurs as the result of a dysregulated host response to an infection,13 a suggestion that has gained general acceptance in recent years.4 Septic shock, the most severe form of sepsis (figure 1), is a form of acute circulatory failure due to sepsis. Septic shock is clinically identified by the presence of hypotension that necessitates vasopressor therapy, and is associated with signs of altered tissue perfusion, such as altered skin perfusion, decreased urine output, and altered mental status. The diagnosis of shock is confirmed by elevated blood lactate levels (greater than 2 mmol/L). Changes in organ function can, of course, be caused by factors other than sepsis, but separation of what is due to sepsis itself and what is due to other elements is difficult. As noted earlier, the presence of infection is not always obvious, so in the clinical situation, it is not always possible to identify sepsis by looking for organ dysfunction in a patient with known infection. More often, the opposite approach is more applicable, with physicians asking whether the new onset of unexplained hypoxaemia, oliguria, thrombocytopenia, or altered mental status suggests that their patient has sepsis—ie, the presence of unexplained, new-onset organ dysfunction should prompt a search for infection (figure 2).
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
Viewpoint
Clinical
Laboratory or treatment-related
Predisposing factors
Age, immunosuppression, comorbidities, alcoholism, drugs, etc
Genetic factors, cellular markers (eg, HLA-DR)
Infection
Signs of pneumonia, meningitis, peritonitis, purpura, etc
Chest x-ray, CT scan, etc Microbiological results, bacterial DNA, endotoxin, etc
Response
Fever, tachycardia, tachypnoea, etc
WBC, CRP, PCT, other sepsis markers
Organ dysfunction
Shock, oliguria, respiratory failure, coagulopathy, etc
Lactate, creatinine, PaO2/FiO2, platelet count
HLA-DR=human leucocyte antigen DR. WBC=white blood cell count. CRP=C-reactive protein. PCT=procalcitonin. PaO2/FiO2=ratio of arterial oxygen partial pressure to fractional inspired oxygen.
Table 2: The predisposing factors, infection, response, organ dysfunction (PIRO) classification model11
Sepsis is clearly more than just an infection that can be identified by the affected organ (eg, pneumonia, urinary tract infection, meningitis) and the type of microorganism (eg, pneumococcal, meningococcal, Candida, herpes virus). Sepsis is a heterogeneous disorder, which can be associated with many different types of infection and several other characteristics. This heterogeneity is why the predisposing factors, infection, response, organ dysfunction (PIRO) classification system was introduced more than 10 years ago to try and provide a framework by which the different components of the complex disease process could be separately characterised (table 2).11 In this model, P represents predisposing factors, including genetics, past history, and clinical context; I includes aspects of the (confirmed or suspected) infectious source and the microorganism responsible (when this information is available); R refers to the patient’s response in terms of vital signs and sepsis markers, such as C-reactive protein, procalcitonin or human leucocyte antigen DR; and O represents the extent of organ dysfunction, based on the six organs whose function can be easily assessed. Another important aspect is to identify sepsis early. The SOFA score is well recognised as a valuable method to characterise organ dysfunction, but it is somewhat complex for early identification of the patient with sepsis outside an ICU setting. In the past year, analyses of large databases showed that three simple elements within the score can provide sufficient information to trigger an alarm signal: tachypnoea, hypotension, and altered mentation. These have been included in what is called a quick SOFA (qSOFA).13 This model has the advantage of being simple and easy to remember. Nurses and other health-care workers on the general floor, who are perhaps not so familiar with the signs of sepsis, might find it particularly useful. In a patient with suspected infection, the qSOFA could thus be used to suggest the need to call for a member of staff who is trained to deal with sepsis, or perhaps a designated sepsis team, to do a panel of laboratory tests (including blood lactate concentrations) to characterise organ dysfunction and to increase surveillance of the patient and arrange transfer to the ICU. Findings from several studies have shown the important role of nurses in detecting early alarm signals,14,15 largely because of their frequent presence at
the patient’s bedside. Importantly, the SOFA (and qSOFA) score reflects both chronic and acute alterations in organ function, so that changes in SOFA scores over time are more useful than a single static value.16 But do we actually need the term sepsis at all? Why can’t we simply refer to the disorder as severe infection? Although this is indeed debatable, we believe the term sepsis is important for two key reasons: first, it stresses the severity of the problem and the need for urgent and vigorous action. Contacting the ICU doctor for a septic patient produces a more urgent response than for a patient with a severe infection, and a rapid reaction is essential to improve outcomes in these life-threatening situations. Early haemodynamic resuscitation is crucial, together with rapid control of infection, which includes not only the prompt administration of broad-spectrum antibiotics to target all likely causative microorganisms, but also a thorough search for a source of infection. Whenever possible, clinicians should be source-specific when using the term sepsis and speak about urinary sepsis, sepsis secondary to pneumonia, and so on. In addition to providing useful management and prognostic information, this approach will encourage us not to be satisfied with a diagnosis of sepsis, but to continue to look for the source of infection. The second reason to keep the term sepsis is because it might help trigger use of a specific therapy to help the patient regain an appropriate host-response. Admittedly, no sepsis-specific therapies are currently available, but effective strategies will undoubtedly be developed in the near future; these strategies were reviewed in a Commission2 in 2015. New sepsis therapies will be more personalised and targeted at a specific pathophysiological alteration (eg, endothelial damage and oedema formation for selepressin), a relevant mediator (eg, coagulopathy for thrombomodulin, blood gelsolin levels for gelsolin administration), or specific organ function (eg, alkaline phosphatase for renal dysfunction, interferon β for lung dysfunction).
Conclusion So, is this new consensus a big step? Not really, but it is a welcome and necessary update. The systemic inflammatory response syndrome was a (long) hiccup in the history of sepsis, and we are now heading back towards a more representative and realistic definition.
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6
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Search strategy and selection criteria We selected relevant literature published in English based largely on our personal knowledge of developments in sepsis research.
Just as monitoring alone cannot improve outcomes,17 altered definitions cannot be said to represent major progress in terms of patient management. Introduction of the new Berlin definitions of acute respiratory distress syndrome18 into an ICU is unlikely to improve the management of severe respiratory failure; similarly with the new definitions of acute kidney injury.19 Perhaps we spend too much time on definitions. Nevertheless, an update of sepsis terminology was long overdue and there was a real need for a usable working definition of sepsis to be established, both for clinical practice and clinical research use.2 This consensus has provided some clarity regarding this still too often fatal disease, such as the importance of the organ dysfunction component and the need for early recognition, which should help to provide a more standardised approach to the identification and management of the patient with suspected sepsis. Contributors J-LV wrote the first draft of the manuscript. J-PM and MA critically revised the text. All authors approved the final version.
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Declaration of interests We declare no competing interests. References 1 Geroulanos S, Douka ET. Historical perspective of the word “sepsis”. Intensive Care Med 2006; 32: 2077. 2 Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015; 15: 581–614. 3 American College of Chest Physicians, Society of Critical Care Medicine. Consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864–74. 4 Vincent JL, Opal S, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet 2013; 381: 774–75.
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Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you… Crit Care Med 1997; 25: 372–74. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372: 1629–38. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 2014; 311: 1308–16. Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution. N Engl J Med 2014; 370: 1673–76. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med 2014; 2: 380–86. Osler W. Pneumonia. In: The principles and practice of medicine, 3rd edn. London: D Appleton and Company, 1898: 109. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250–56. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/ failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707–10. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; published online Feb 22. DOI:10.1001/ Jama.2016.0287. Gyang E, Shieh L, Forsey L, Maggio P. A nurse-driven screening tool for the early identification of sepsis in an intermediate care unit setting. J Hosp Med 2015; 10: 97–103. Douw G, Schoonhoven L, Holwerda T, et al. Nurses’ worry or concern and early recognition of deteriorating patients on general wards in acute care hospitals: a systematic review. Crit Care 2015; 19: 230. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001; 286: 1754–58. Vincent JL, Rhodes A, Perel A, et al. Clinical review: update on hemodynamic monitoring—a consensus of 16. Crit Care 2011; 15: 229. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Kidney Disease Improving Global Outcomes Acute Kidney Injury Work Group. Kidney Disease Improving Global Outcomes Clinical practice guideline for acute kidney injury. Section 2: AKI definition. Kidney Int Suppl 2012; 2: 19–36.
www.thelancet.com/respiratory Published online February 22, 2016 http://dx.doi.org/10.1016/S2213-2600(15)00522-6