How do I identify the patient with “sepsis”?

31 How Do I Identify the Patient With “Sepsis”? Craig M. Coopersmith and Katherine Lyn Nugent

SEPSIS-1 AND SEPSIS-2 The ability to identify a patient with sepsis is directly related to the ability to define sepsis. It has been acknowledged that, as recently as the 1980s, the lack of a consensus definition of sepsis limited the ability of medical providers to identify and treat septic patients. In 1992, an American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) consensus conference provided the first comprehensive approach to defining sepsis.1 A critical portion of the definition was the use of the systemic inflammatory response syndrome (SIRS) criteria. SIRS was a response to a variety of severe clinical insults (infectious and not-infectious) and contained four elements: • heart rate .90 beats per minute • respiratory rate .20 breaths per minute or a pCO2 ,34 mm Hg • white blood cell count .12,000/mm3 or ,4,000 mm3, and • temperature .38°C or ,34°C. Sepsis was defined as at least two of four SIRS criteria in the setting of suspected infection. Severe sepsis was defined as sepsis plus organ dysfunction, hypoperfusion or hypotension. Septic shock was defined as sepsis plus hypotension resistant to fluid resuscitation in the presence of perfusion abnormalities including, but not limited to, lactic acidosis, oliguria or an acute alteration in mental status. Eleven years later, a second attempt was made to define sepsis via a consensus conference involving the SCCM, ACCP, the European Society of Intensive Care Medicine (ESCIM), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS).2 Despite the passage of time and new insights into the pathophysiology of sepsis, little changed in the definition of sepsis as the authors concluded that apart from expanding the lists of signs and symptoms of sepsis to better reflect bedside experience, a lack of new evidence precluded updating the definition. Of note, the authors did propose use of the predisposition, insult/infection, response, organ dysfunction (PIRO) staging system as an intellectual construct for future sepsis research. Although the elements within this hypothesis-generating model would be incorporated into future thought on sepsis, PIRO did not gain widespread usage. The definitions from these two consensus conferences (now termed Sepsis-1 and Sepsis-2) served the medical

community well for nearly a quarter century. Indeed, an explosion of sepsis studies used this common framework for the disease. Unfortunately, numerous limitations to the definitions were identified over time. First, the “definition” of sepsis was not actually a definition. The term “definition” is described in the dictionary as “the essential nature of a thing” or, more succinctly, “what something is.” Sepsis-1 and Sepsis-2 did not meet this criterion—in reality, they were bedside tools for identifying patients with the syndrome. By analogy, an elevated troponin is a biomarker for a myocardial infarction, but it does not define the disorder. Other problems also existed with Sepsis-1 and Sepsis-2. First, the term “severe sepsis” was controversial because it implied that there was also a nonsevere form of the disease. Considering the high mortality associated with sepsis, the possibility that a clinician might conclude that there is a nonsevere form of sepsis has potential direct effects on patient outcome. Medical providers might not see this as an acute, time-sensitive condition, leading to delays in treatment and increased mortality. Finally, the concept of SIRS came under significant criticism for a variety of reasons.3 Studies indicated that at least 50% of patients developed SIRS at some point during their hospitalization, limiting its utility for specifically identifying patients with sepsis.4 Perhaps more concerning was the finding that in a retrospective analysis of over 100,00 patients admitted to the intensive care unit (ICU), 1 out of 8 did not have two SIRS criteria despite confirmed infection and similar organ dysfunction as patients with two or more SIRS criteria.5 Intellectually, there was also a concern that SIRS generally represented an adaptive response to any inflammatory insult, whereas sepsis represents a maladaptive response to infection. It seems questionable to define a disease in large part by a body’s appropriate response to an insult.

SEPSIS-3: AN INTELLECTUAL ADVANCE Based upon these concerns, as well as those that Sepsis-1 and Sepsis-2 focused disproportionately on systemic inflammation in the pathophysiology of the disease process, SCCM and ESICM assembled the Third International Consensus Definitions Task Force for Sepsis and Septic shock (Sepsis-3).6 This task force redefined sepsis as “life-threatening organ 221

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dysfunction caused by a dysregulated host response to infection.” A number of changes to the concept of sepsis were made explicit (and implicit) in this new definition. First, after being part of how sepsis was defined for a quarter century, the SIRS criteria were eliminated from the new definition of sepsis. SIRS, as a concept, has face validity for the diagnosis of infection, but this is distinct from diagnosing sepsis. Next, the new definition recharacterized the disorder. The physiologic state formerly termed “sepsis” (with SIRS but without organ dysfunction) now represents “systemic infection” alone and not “sepsis” given the concept of organ dysfunction was absent from the previous definition. This change not only eliminated a significant population of patients from being classified as septic when they lacked organ dysfunction but also highlighted the characterization of sepsis as preventable; infected patients treated rapidly with antibiotics might never develop organ dysfunction. The next change in Sepsis-3 was the elimination of the term, “severe sepsis.” Sepsis is now life threatening by definition, acknowledging its severity at all times. Notably, no change was made to the definition of infection, which the task force felt was beyond its scope, and continues to refer to “a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms.” Sepsis-3 also redefined septic shock as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Similar to sepsis, the “definition” of septic shock in Sepsis-1 and Sepsis-2 was actually a bedside tool to recognize the disease, and the redefinition of septic shock more accurately reflects the essential nature of the disorder. In addition, Sepsis-3 extends the definition of septic shock by emphasizing the pathobiological role of cellular and metabolic abnormalities in circulatory dysfunction.

SEPSIS-3 AT THE BEDSIDE While the definitions of sepsis and septic shock represent an intellectual advance, they are unhelpful at the bedside. As such, in order to rapidly identify patients with sepsis, clinical criteria were required. To be useful to the bedside clinician, these criteria must reflect the components of the definition— a threat to life, organ dysfunction, and abnormal host response to infection—while simultaneously differentiating patients with sepsis from those without with acceptable sensitivity and specificity. Additionally, high criterion validity (as achieved by more complex scoring systems involving a larger number of clinical or laboratory variables) needed to be balanced with the value placed on low encumbrance for the bedside clinician. Furthermore, a high value was placed on the timeliness of identification. This last was critical given the link between syndrome identification and management. Considering this direct link between sepsis and septic shock management and outcomes,7–10 the clinical criteria for sepsis and septic shock had to be simple enough that bedside clinicians could rapidly identify at-risk patients.

The clinical criteria used for the recognition of sepsis are the presence of suspected or confirmed infection and a Sequential Organ Failure Assessment (SOFA, also known as the Sepsis-related Organ Failure Assessment) score of 2. The baseline SOFA score is assumed to be zero in patients not known to have preexisting organ dysfunction, even if no history is available. The SOFA score wasn’t created for use in Sepsis-3. Rather, it was unveiled in 199411 as a simple, easily determined index composed of objective, routinely measured variables. The SOFA score could be followed over time to map the natural course of a disease or to assess the influence of therapeutic interventions. The score is comprised of a combination of laboratory values, physical exam characteristics, and clinical interventions aimed at grading the level of dysfunction of six different organ systems (Table 31.1). While the SOFA score was not designed to predict outcomes, a rise in the SOFA score 24 hours after the initial score is calculated has been associated with an increased probability of mortality.12 SOFA is more complicated than SIRS, but is relatively easy to calculate and represents a reasonable approach to the quantification of organ dysfunction, allowing for rapid clinical operationalization of the new sepsis definition. The Sepsis-3 criteria were explicitly compared to SIRS and, in the data sets examined, had both superior sensitivity and specificity. The clinical criteria for septic shock allow for identification of this state by utilizing a construct in which patients have (1) hypotension requiring vasopressors to maintain a mean arterial pressure .65 mm Hg and (2) a serum lactate .2 mmol/L despite adequate fluid resuscitation. It is important to note that, in contrast to previous approaches to septic shock, the Sepsis-3 clinical criteria were derived and validated via analysis of over 3 million hospital charts.13 In this analysis, mortality was 42% in patients meeting all criteria. In those who were hypotensive/vasopressor dependent but had a lactate , 2 mmol/L, mortality was 30%, while patients not requiring vasopressors who had an elevated lactate had a mortality rate of 26%. It is important to note which criteria are used when reading the literature because the change from Sepsis-1 to Sepsis-3 alters which patients are identified as septic. This difference has the potential to change clinical trial results when different criteria are applied to an identical patient cohort.14

qSOFA: A NEW SCREENING TOOL FOR SEPSIS Perhaps the most misunderstood aspect of Sepsis-3 was the introduction of the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) score.7 This new screening tool has three components: • systolic hypotension (,100 mm Hg), • tachypnea (respiratory rate 22 breaths per minute), and • altered mentation (as assessed by a Glasgow Coma Scale of 13 or less).

CHAPTER 31

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TABLE 31.1  ​The SOFA Score. SOFA Score

1

2

3

4

Respiration PaO2/FiO2a mmHg

,400

,300

,200

,100

——with respiratory support—— Coagulation Platelets ×103/mm3

,150

,100

,50

,20

1.2–1.9 (20–32)

2.0–5.9 (33–101)

6.0–11.9 (102–204)

.12.0 (,204)

Cardiovascular Hypotension

MAP ,70 mmHg

Dopamine # 5 or dobutamine (any dose)a

Dopamine .5 or epinephrine #0.1 or norepinephrine #0.1

Dopamine .15 or epinephrine .0.1 or norepinephrine .0.1

Central Nervous System Glasgow Coma Score

13–14

10–12

6–9

,6

Renal Creatinine, mg/dl (mmol/l) or urine output

1.2–1.9 (110–170)

2.0–3.4 (171–299)

3.5–4.9 (300–440) or ,500 ml/day

.5.0 (.440) or ,200 ml/day

Liver Bilirubin, mg/dl (mmol/l)

Adrenergic agents administered for at least 1 h (doses given are in µg/kg • min)

a

qSOFA was derived from a large electronic health record and validated in several additional databases. Overall, more than 7 million patient charts were examined. From the initial dataset, patients with suspected, presumed or documented infection were identified. Because there is no “gold standard” for diagnosing sepsis, the combination of death and/or ICU stay 3 days served as a proxy. Each of the variables compiled in Sepsis-2 for their value in identifying patients with sepsis was examined, alone or in combination, for the ability to predict the proxy. Patients in whom 2 of the 3 components of qSOFA were present had a 3- to 14-fold increase in in-hospital mortality across baseline risk deciles relative to patients whose qSOFA score was ,2. Adding a serum lactate level 2.0 mmol/L to the three qSOFA variables did not increase predictive validity. Of note, the qSOFA score was derived and validated in over 7 million patient charts. Importantly, qSOFA is a screening tool to be used to identify septic patients in whom further work up may be warranted. It is not intended to be an alternative to the SOFA score as an approach to clinical criteria for sepsis. Indeed, the utility of qSOFA varied by location within the hospital. In patients outside of the ICU, the qSOFA score was found to have similar areas under the curve for in-hospital mortality as SOFA. In contrast, for patients inside the ICU, SOFA had a predictive validity that was superior to qSOFA. Of note, in the datasets examined, the SIRS score had a lower predictive validity for in-hospitality mortality than qSOFA and SOFA regardless of whether the patient was in the ICU or not. A key attribute of qSOFA is its simplicity. In contrast to SOFA or other more complex scoring systems, qSOFA

consists of only three elements, each of which is easily measured at the bedside. No laboratory tests are needed. However, while the simplicity of qSOFA is attractive, it has generated significant criticism.15,16 Much of it surrounded a concern that patients are quite ill by the time they have a qSOFA score of 2, which could delay intervention. Further, the primary outcome driving the development and validation of qSOFA was in-hospital mortality, one of only multiple outcomes of interest in sepsis screening, especially in the emergency department. Finally, while emergency medicine providers use screening tools to not only identify patients with possible sepsis but also to assist with triaging the sickest patients from a large census, to initiate time-sensitive interventions, and to help with disposition planning, sSOFA was derived and validated in patients with suspected, presumed or documented infection. The validity of qSOFA in evaluation of patients with other underlying disorders has not been tested. In addition, the clinical criteria derived in Sepsis-3 do not include any treatment recommendations for the management of sepsis or septic shock.

WHAT HAS HAPPENED SINCE SEPSIS-3? The Sepsis-3 manuscript has been viewed over 2.5 million times on the JAMA website and has been cited over 2000 times.6 Because the original clinical criteria were based on analysis of a large database in a manner that had not previously been performed, the authors explicitly stated that clinical criteria and qSOFA required additional validation. There were over 150 publications on qSOFA in the first 2 years following the publication of Sepsis-3. Most are

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directed at comparing the Sepsis-3 criteria, either SOFA or qSOFA, with other approaches, most often Sepsis-1 (i.e., SIRS). Some17,18 have supported the results of aspects of Sepsis-3,7 others12,17,19 have not. A number of studies have compared Sepsis-3 criteria to approaches other than Sepsis-1.15,20,21 Many have focused on outcomes other than those used in Sepsis-3. Perhaps the most salient with respect to Sepsis-3 criteria in the ICU examined patients in the Case Mix Programme Database, a national clinical audit for adult admissions to general ICUs in England.22 Among patients admitted to the ICU for infection, 197,724 met Sepsis-2 criteria for severe sepsis while 197,142 met Sepsis-3 criteria and 189,243 met both definitions, a 92% overlap. Differences in mortality and ICU length of stay were not statistically significant. What this study illustrates is an issue that arises with virtually all such reports—difficulty in comparing false positives (patients who met either set of criteria but did not meet outcome criteria) and false negatives (patients who did not meet either set of criteria but did meet outcome criteria). The need to validate Sepsis-3 criteria in middle- and lowincome countries was specifically cited as a deficit by the Sepsis-3 Task Force. A 2018 metaanalysis of nine studies of qSOFA in low- and middle-income countries demonstrated that qSOFA identified patients at risk of death beyond that explained by baseline factors and was superior to SIRS.23 In a single institution study, Matics and Sanchez-Pinto validated an age-adjusted qSOFA score.24

CONCLUSION Identifying patients with sepsis is problematic, especially given the lack of a gold-standard for comparison. Thus, inter-observer variability becomes important. The difficulty is exemplified by the results of a survey distributed to 94 physicians (the majority of whom were critical care medicine specialists). When asked to evaluate five clinical vignettes of patients with suspected or confirmed infection and organ dysfunction, the variable results demonstrated the subjective nature of diagnosing sepsis regardless of participants’ perceived confidence in sepsis-related definitions or clinical experience.25 Further complicating matters is the fact that there is more than one set of clinical criteria currently in use. It has been proposed that different definitions may be useful for different purposes including clinical care, clinical trials, basic research, surveillance, and quality improvement/audit.26 The usefulness of these definitions can be measured by six criteria that vary widely depending upon the context of the definition (1) reliability, (2) content validity, (3) construct validity, (4) criterion validity, (5) measurement burden and (6) timeliness.27 Ultimately, different classification criteria may identify different incidences of sepsis with different mortalities.28 Each definition has inherent strengths and weaknesses, and an approach using more than one set of clinical criteria may balance the sensitivity and specificity needed in identifying septic patients.29

AUTHORS’ RECOMMENDATIONS • The Sepsis-3 formulation provided new, clinically validated criteria for identifying patients likely to have sepsis or septic shock. These criteria have been designed to supersede SIRS-based criteria. The new clinical criteria are based on use of the SOFA score. • A prompt designed to alert clinicians of a need for additional evaluation, qSOFA, was also derived and validated de novo. • Studies conducted since the publication of Sepsis-3 have examined the value of SOFA and qSOFA relative to Sepsis-1 criteria and a number of additional assessment methods. • Current data suggest that Sepsis-3 criteria are effective in low- and middle-income countries. A single study suggests the value of an age-adjusted qSOFA score in children.

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CHAPTER 31 12. Raith EP, Udy AA, Bailey M, et al. Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA. 2017;317(3):290-300. 13. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775-787. 14. Russell JA, Lee T, Singer J, Boyd JH, Walley KR. The Septic Shock 3.0 definition and trials: a vasopressin and septic shock trial experience. Crit Care Med. 2017;45(6):940-948. 15. Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med. 2017;195(7):906-911. 16. Hwang SY, Jo IJ, Lee SU, et al. Low accuracy of positive qSOFA criteria for predicting 28-day mortality in critically ill septic patients during the early period after emergency department presentation. Ann Emerg Med. 2018;71(1):1-9.e2. 17. Fang X, Wang Z, Yang J, et al. Clinical evaluation of Sepsis-1 and Sepsis-3 in the ICU. Chest. 2018;153(5):1169-1176. 18. Freund Y, Lemachatti N, Krastinova E, et al. Prognostic accuracy of Sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317(3):301-308. 19. Song JU, Sin CK, Park HK, Shim SR, Lee J. Performance of the quick Sequential (sepsis-related) Organ Failure Assessment score as a prognostic tool in infected patients outside the intensive care unit: a systematic review and meta-analysis. Crit Care. 2018;22:28. 20. Wang JY, Chen YX, Guo SB, Mei X, Yang P. Predictive performance of quick Sepsis-related Organ Failure Assessment for mortality and ICU admission in patients with infection at the ED. Am J Emerg Med. 2016;34:1788-1793. 21. Chen YX, Wang JY, Guo SB. Use of CRB-65 and quick Sepsisrelated Organ Failure Assessment to predict site of care and

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mortality in pneumonia patients in the emergency department: a retrospective study. Crit Care. 2016;20(1):167. 22. Shankar-Hari M, Harrison DA, Rubenfeld GD, Rowan K. Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database. Br J Anaesth. 2017;119: 626-636. 23. Rudd KE, Seymour CW, Aluisio AR, et al. Association of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score with excess hospital mortality in adults with suspected infection in low- and middle-income countries. JAMA. 2018;319(21):2202-2211. 24. Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children. JAMA Pediatr. 2017;171(10):e172352. 25. Rhee C, Kadri SS, Danner RL, et al. Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes. Crit Care. 2016;20:89. 26. Seymour CW, Coopersmith CM, Deutschman CS, et al. Application of a framework to assess the usefulness of alternative sepsis criteria. Crit Care Med. 2016;44:e122-e130. 27. Angus DC, Seymour CW, Coopersmith CM, et al. A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med. 2016;44(3): e113-e121. 28. Donnelly JP, Safford MM, Shapiro NI, Baddley JW, Wang HE. Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) Classification: a retrospective population-based cohort study. Lancet Infect Dis. 2017;17(6):661-670. 29. Serafim R, Gomes JA, Salluh J, Póvoa P. A comparison of the quick-SOFA and systemic inflammatory response syndrome criteria for the diagnosis of sepsis and prediction of mortality: a systematic review and meta-analysis. Chest. 2018;153(3):646-655.

e1 Abstract: Identification of a patient with sepsis requires both a definition and validated clinical criteria. At the first of three consensus conferences to identify the syndrome, sepsis was defined as at least two of four systemic inflammatory response syndrome (SIRS) criteria in the setting of suspected infection. The definitions of sepsis, severe sepsis, and septic shock were revisited in 2001 and most recently in 2016 in the Third International Consensus Definitions Task Force for Sepsis and Septic shock (Sepsis-3). This task force redefined sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection,” eliminated the SIRS criteria both in defining sepsis and identifying patients with sepsis, and eliminated the term “severe sepsis” owing to

evidence that all sepsis is severe. Sepsis-3 also introduced the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) score as a screening tool to be used to help identify septic patients who are more likely to have poor outcomes. qSOFA was compared to other, more complicated scoring systems including SOFA and LODS and was found to have a similar predictive value for mortality, specifically in patients outside the intensive care unit. Each definition and set of clinical criteria has inherent strengths and weaknesses, and the lack of a gold standard approach to identifying patients with sepsis or septic shock highlights the need for further research. Keywords: sepsis, Sepsis-3, septic shock, SIRS, SOFA, qSOFA