Sepsis Definitions and Diagnosis

OVERVIEW

The original definitions of sepsis and related conditions (SIRS, severe sepsis and septic shock) are now more than 20 years old (Sepsis- 1 originated from the ACCP/SCCM consensus meeting in 1991 and Sepsis 2 from 2001)

• Clinicians (in Australasia at least) generally did not explicitly use SIRS criteria to make the diagnosis of sepsis, despite the existence of SIRS-based definitions

A new definition of sepsis has now been published (see ‘Sepsis 3’ below)

• the layperson description is that sepsis is ‘a life-threatening condition that arises when the body’s response to infection injures its own tissue’
• ‘severe sepsis’ no longer exists as a concept, there is simply ‘sepsis’ and ‘septic shock’
• the new ‘Sepsis 3’ definition was created by the ESICM-SCCM Sepsis Redefinitions Task Force

Advances in the treatment of fever … have not kept pace with the rapid progress in our knowledge of the etiology. In the present condition of bacteriology we may expect great things in the near future, but meanwhile we jog along without any fixed aim, too often carried away by winds of doctrines and wild theories

William Osler. The study of the Fevers of the South. JAMA 1896; 21: 999–1004

SEPSIS 3 DEFINITIONS

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection

• Sepsis clinical criteria: organ dysfunction is defined as an increase of 2 points or more in the Sequential Organ Failure Assessment (SOFA) score
  • for patients with infections, an increase of 2 SOFA points gives an overall mortality rate of 10%
• Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA (“HAT”); i.e. 2 or more of:
  • Hypotension: SBP less than or equal to 100 mmHg
  • Altered mental status (any GCS less than 15)
  • Tachypnoea: RR greater than or equal to 22

Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.

• Septic shock clinical criteria: Sepsis and (despite adequate volume resuscitation) both of:
  • Persistent hypotension requiring vasopressors to maintain MAP greater than or equal to 65 mm Hg, and
  • Lactate greater than or equal to 2 mmol/L
• With these criteria, hospital mortality is in excess of 40%

Not that the term “severe sepsis” is no longer in use.

PROBLEMS WITH SEPSIS 3

Immediately following the publication of the Sepsis 3 definition, potential problems have been highlighted:

• Sepsis 3 did not involve low/ middle income countries (LMIC), where raising awareness and early detection are priorities
  • e.g. patients with isolated hypotension or a reduced level of consciousness will be classified as “uncomplicated infection”
• SOFA is a complicated score that is routinely calculated in some ICUs, but is not explicitly used in others (e.g. many Australian ICUs use APACHE scores instead)
  • The baseline SOFA score is assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ dysfunction before the onset of infection
  • SOFA has the limitations characteristic of a categorical ordinal scale
• The use of the qSOFA score is potentially problematic, despite having predictive validity (AUROC = 0.81; 95% CI, 0.80-0.82) similar to that of the full SOFA score outside the ICU
  • qSOFA has only been validated retrospectively, based on data from the USA and Germany
  • qSOFA has not been demonstrated to be useful in the wide range of clinical settings that sepsis is encountered
  • ‘new onset’ versus ‘established’ qSOFA points are unknown
  • the authors of Sepsis 3 note that addition of lactate measurement did not meaningfully improve predictive validity of qSOFA but may help identify patients at intermediate risk
• The data set of 148 907 patients that the definition is based on were those with suspected infection who had body fluids sampled for culture and received antibiotics – would mortality be higher if they had not received antibiotics? Can this be extrapolated to patients who are yet to receive antibiotics?
• Sepsis 3 is not endorsed by ACEP or SAEM in the USA as emergency providers were not included in the task force
• Sepsis 3 is (apparently) endorsed by ANZICS in Australasia, but the task force did not involve CICM or ACEM
• It is unclear how to interpret previous studies (e.g. Rivers et al 2001, ProCESS, PROMISE, and ARISE) in light of the new definitions

Comparison with SIRS

• In the data set used to retrospectively validated the Sepsis 3 criteria:
  • In ICU patients with suspected infection, SOFA (AUROC = 0.74; 95% CI, 0.73-0.76) was superior to SIRS (AUROC = 0.64; 95% CI, 0.62-0.66) for predicting hospital mortality
  • In patients outside of the ICU, SOFA (AUROC = 0.79; 95% CI, 0.78-0.80) or change in SOFA score (AUROC = 0.79; 95% CI, 0.78-0.79) was similar to that with SIRS (AUROC = 0.76; 95% CI, 0.75-0.77) for predicting hospital mortality

PREVIOUS SURVIVING SEPSIS CAMPAIGN DEFINITION

Systemic inflammatory response syndrome (SIRS) requires 2 or more of the following (the definition differs for children):

1. T >38 C or <36 C
2. P >90/min
3. RR >20/min or PaCO2 <32 mmHg
4. WCC >12 or >10% immature band forms

Sepsis

• Sepsis is SIRS + confirmed or presumed infections
• mortality: 10-15%

Severe Sepsis

• Severe Sepsis is sepsis with organ dysfunction
• organ dysfunction includes:
  • SBP <90 mmHg or MAP < 65 mmHg or lactate > 2.0 mmol/L (after initial fluid challenge)
  • INR >1.5 or a PTT >60 s
  • Bilirubin >34 µmol/L
  • Urine output <0.5 mL/kg/h for 2 h
  • Creatinine >177 µmol/L
  • Platelets <100 ×109/L
  • SpO2 <90% on room air
• mortality: 17-20%

Septic Shock

• Septic shock is defined as sepsis with refractory hypotension
  • hypotension is defined as SBP <90 mmHg or MAP <70 mmHg
  • refractory means that hypotension persists after 30 mL/kg crystalloid; i.e. vasopressor dependence after adequate volume resuscitation
• mortality: 43-54%

PROBLEMS WITH DEFINITIONS BASED ON SIRS CRITERIA

• The terminology used does not promote an understanding the underlying problem or disease process (lack of face validity)
  • a key feature of sepsis is that it involves a host response to infection that is maladaptive, and injuries the host’s own organs and tissues
  • ‘Septic shock’ requires refractory hypotension to be present, however hypotensive patients do not necessarily have shock (globally impaired tissue perfusion) and patients in shock may not be hypotensive
• SIRS lacks sensitivity for defining sepsis (at least in patients admitted to ICU)
  • 1 in 8 ICU patients with infection and organ dysfunction do not have 2 or more SIRS critieria
• SIRS not specific
  • 4 in 5 ICU patients without infection have ‘SIRS’ criteria
• SIRS does not reflect the severity of the disease process (lack of construct validity)
  • the odds ratio for mortality increases incremental with additional SIRS criteria (from 1, to 2, to 3, to 4) without a step up when the definition of SIRS is met (2 criteria)
• SIRS may detract from the search for an infection
• Definitions lack content validity:
  • hypotension and hyperlactaemia are inadequate proxies for septic cardiomyopathy and shock
• Definitions lack criterion validity
  • prognosis varies depending on how the sepsis definitions are applied (lack of predictive validity)
  • different sources of infection are associated with different mortality rates
• SIRS criteria do not account for the dynamic time-course of sepsis (e.g. rise and fall in white cell count over time, fluctuations in vital signs)
• patients with mild influenza can potentially meet SIRS criteria
• SIRS parameters are arbitrarily simplified (e.g. heart rate of 90 and WBC count of 10 have no true physiological significance as thresholds)

PROBLEMS IN THE DIAGNOSIS OF SEPSIS

The diagnosis of sepsis is confirmed using both clinical and laboratory information

Clinical

• fever and other SIRS criteria have a low specificity (e.g. burns, pancreatitis, transfusion)
• SIRS may simply reflect an appropriate host response that is frequently adaptive; rather than a dysregulated host reaction resulting in organ dysfunction that is the sine qua non of sepsis
• SIRS is insensitive in ICU patients for diagnosing ‘infection + organ dysfunction’ (Kaukonnen et al, 2015)
• no specific clinical signs of sepsis
• elderly, immunocompromised and malnourished patients do not manifest typical signs of sepsis or SIRS
• both infective and non-infective SIRS can co-exist in same patient
• deep seated collections and ‘hidden causes’ may be difficult to diagnose
• some of the clinical criteria applies to adult physiological variables
• the presence of infection may never be confirmed even when presence (culture negative sepsis)
• qSOFA has not been prospectively validated and requires the presence of at least 2 concerning signs/ sympotms

Laboratory

• increased WCC is a marker of stress rather than just infection
• isolated findings can take place for other reasons (e.g. steroids -> increased WCC)
• reliant on documented bacteraemia or collection of organisms from sterile tissue (tissue can be hard to collect or require invasive measures)
• distinguishing colonisation versus infection may be difficult (e.g. PJP PCR from BAL)
• early administration of antibiotics is important in management but decreases diagnostic yield
• delay in diagnosis (time until culture results available)
• specimens are easily contaminated
• PCR tests are not universally available
• serology is non-specific and generally requires convalescent tests and repeat tests after 2 weeks
• biomarkers such as CRP, IL-6 and procalcitonin have limited sensitivity & specificity and cannot be used in isolation
• lack of consensus on what constitutes different illness (ie. ventilatory acquired pneumonia, line sepsis)

Sepsis is a dynamic condition with clinical and laboratory manifestations that change over time, all criteria may not be present at a single time

EVIDENCE

Summary

• The sepsis 3 definition is based on the qSOFA score that was derived and retrospectively validated in a cohort of 148,907 patients (Shankar-Hari et al, 2016)
• A retrospective analysis by Kaukonnen et al (2015) suggested that SIRS criteria lacked specificity and sensitivity for diagnosing severe sepsis / septic shock

Kaukonnen et al, NEJM 2015

• Retrospective analysis of the ANZICS Adult Patient Database of 172 ICUs in Australia and New Zealand
• Included 109,663 patients with diagnosed infection with organ dysfunction (formerly severe sepsis and septic shock)
• Findings:
  • 87.9% had 2 or more SIRS criteria
  • 12.1% did not have 2 or more SIRS criteria
  • Using SIRS alone will miss 1 in 8 patients with severe sepsis
  • Each additional SIRS Criteria increased mortality by 13% in a linear fashion without a transitional increase when 2 criteria were met
• Criticisms and commentary:
  • lack of a standardised definition of sepsis – this study
  • limited to data from the first 24 hours of ICU admission only
  • database registries are susceptible to entry errors and misclassification bias
  • did not assess PaCO2 <32 mmHg or >10% immature band forms
  • may not be externally valid to settings other than the ICU
•  Conclusions
  • the use of ≥2 SIRS criteria alone lacks both sensitivity and specificity for diagnosing severe sepsis in patients admitted to ICU

CONCLUDING REMARKS

• The clinical utility of the new Sepsis 3 definition remains to be seen
• The lack of a reliable definition of sepsis makes assessment of incidence and changes in outcomes difficult to quantify reliably
• There may be value in using a screening test for sepsis (highly sensitive) and a confirmatory test (highly specific), perhaps involving new sepsis biomarkers or continuous data for staging rather than ‘all or none’ dichotomous data
• Ideally definitions should be useful to both clinicians and researchers
• Consider sepsis as a possible cause whenever a patient develops new organ dysfunction
• If concerned about a patient with severe infection do not withhold therapy for sepsis just because qSOFA criteria are not met (see ‘Problems with Sepsis 3’)
  • qSOFA criteria should prompt (1) consideration of infection as an underlying cause, (2) investigation for further organ dysfunction, and (3) sepsis management and referral where appropriate

References and Links

LITFL

• CCC — APACHE versus SOFA scores
• CCC — ICU scoring Systems
• CCC — Initial Management of Sepsis and Septic Shock
• CCC — Surviving Sepsis Campaign Guidelines 2012

Journal articles 

• Abraham E. New Definitions for Sepsis and Septic Shock. JAMA. 315(8):757-. 2016. [article]
• Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. PubMed PMID: 23984731. [article]
• Beesley S, Lanspa M. Why we need a new definition of sepsis. Annals of Translational Medicine. 2015;3(19). Available at: http://www.atmjournal.org/article/view/8206/9001. Accessed December 19, 2015.
• Dellinger RP, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. PubMed PMID: 23353941.
• Gaieski DF, Goyal M. What is sepsis? What is severe sepsis? What is septic shock? Searching for objective definitions among the winds of doctrines and wild theories. Expert Review of Anti-infective Therapy. 11(9):867-871. 2013. [article]
• Iwashyna TJ, Govindan S. Did they just prove that a diagnosis of “septic shock” is meaningless? American journal of respiratory and critical care medicine. 189(10):1156-7. 2014. [pubmed] [free full text]
• Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. The New England journal of medicine. 372(17):1629-38. 2015. [pubmed]
• Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ. 2007 Oct 27;335(7625):879-83. Review. PubMed PMID: 17962288; PubMed Central PMCID: PMC2043413.
• Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6. [PubMed] [free full text]
• Lynn LA. The diagnosis of sepsis revisited – a challenge for young medical scientists in the 21st century. Patient safety in surgery. 8(1):1. 2014. [pubmed] [free full text]
• Shankar-Hari M, Bertolini G, Brunkhorst FM, et al. Judging quality of current septic shock definitions and criteria. Critical care. 19(1):445. 2015. [pubmed] [free full text]
• Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis? Intensive care medicine. 41(5):909-11. 2015. [pubmed] [free full text] [free full text]
• Singer  M, Deutschman  CS, Seymour  CW,  et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 doi:10.1001/jama.2016.0287.
• Seymour  CW, Liu  VX, Iwashyna  TJ,  et al.  Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA.2016 doi:10.1001/jama.2016.0288.
• 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 doi:10.1001/jama.2016.0289.
• Vandijck D, Decruyenaere JM, Blot SI. The value of sepsis definitions in daily ICU-practice. Acta clinica Belgica. 61(5):220-6. 2007. [pubmed] [free full text]

FOAM and web resources

• CCR Meeting 2015 — Sepsis 3 Definition by Clifford Deutschman (2015)
• EMCrit — Severe Sepsis Resources
• Esicm.org. REVIEW OF THE SEPSIS-3 ARTICLES. 2016. Available at: http://www.esicm.org/news-article/ARTICLE-REVIEW-sepsis-3-DePascale. Accessed February 24, 2016.
• HealthManagement.org — ISICEM15: SIRS and Sepsis: An Unhappy Marriage (2015)
• SMACC — Sepsis SMACCDOWN (2015)
• FOAMcast — Sepsis Redefined (2015)