What is sepsis? What is severe sepsis?What is septic shock? Searching forobjective definitions among the windsof doctrines and wild theoriesExpert Rev. Anti Infect. Ther. 11(9), 867–871 (2013)

David F GaieskiAuthor for correspondence:

Department of Emergency

Medicine, Perelman School of

Medicine at the University of

Pennsylvania, Center for

Resuscitation Science, 34th and

Spruce Streets, Ground Ravdin,

Philadelphia, PA 19104, USA

Tel.: +1 215 349 5241

Fax: +1 215 662 3953

David.Gaieski@uphs.upenn.edu

Munish GoyalGeorgetown University School of

Medicine, Emergency Intensive

Care, MedStar Washington

Hospital Center, Washington,

DC, USA

“Advances in the treatment of fever … have not kept pace withthe rapid progress in our knowledge of the etiology. In the

present condition of bacteriology we may expect great things inthe near future, but meanwhile we jog along without anyfixed aim, too often carried away by winds of doctrines

and wild theories”.—William Osler [1].

More than 100 years ago, William Oslerobserved: ‘Except on few occasions, thepatient appears to die from the body’sresponse to infection rather than from… [the infection itself]’ [2]. Osler madethis observation in an era prior to theknowledge of the immune system, thesystemic inflammatory response syn-drome (SIRS) or insights into the use ofbiomarkers as a screening tool. It isimportant to understand the history ofmodern sepsis definitions and how theyrelate to early recognition and appropri-ate treatment. We believe that anothersystematic attempt at defining a singleway of identifying and classifyingpatients with life-threatening infectionsis needed.

The practicalities of sepsis manage-ment require rapid identification and treat-ment in patients with severe sepsis andseptic shock. Triage – from the Latinword, tria, or three, meaning, ‘to sort intothree categories’ – attempts to sort patientsbased on severity. Triage is usually associ-ated with the Emergency Department(ED), but the same principles apply to riskstratification elsewhere. The SIRS–sepsis–severe sepsis – septic shock continuum(hereafter referred to as ‘the SIRS–septic shock continuum’; TABLE 1) was born

in 1992 of the hope – yes, more hopethan science – that these categories corre-sponded closely to clinical reality. Subse-quently, there has been increasingrecognition of the time-sensitive nature ofthe diagnosis and management of severeinfections [3–5] and of the difficulties ofrapidly and accurately identifying a signif-icant percentage of these cases [6].

Why is this so important? DerekAngus’s classic study of the epidemiol-ogy of sepsis in the United States pro-vides the frequently quoted estimate that751,000 individuals with severe sepsisare hospitalized annually, approximately215,000 of whom die [7]. Internation-ally, 1,400 severe sepsis patients diedaily [8]. These numbers may, in fact,grossly underestimate the burden ofsevere sepsis seen in the United States:Gaieski et al., using ICD-9 codes forinfection, organ dysfunction and severesepsis assigned by medical record codersat hospital discharge, reported that severesepsis affects between one and three mil-lion people annually in the United Stateswith mortality of 14.7–29.9% dependingupon the technique used to identifycases [9]. Furthermore, the correlationbetween these codes, physician docu-mentation and patients with severe sepsis

Editorial

www.expert-reviews.com 10.1586/14787210.2013.829633 � 2013 Informa UK Ltd ISSN 1478-7210 867

captured by trained clinical researchers has been debated. Usinga database of 1,735 severe sepsis and septic shock cases admit-ted from the ED in an academic medical center,Whittaker et al. demonstrated a low level of capture of thesepatients at hospital discharge by severe sepsis-specific and septicshock-specific ICD-9 billing codes (21.5% overall; 49.5% forseptic shock cases); also, the Angus technique was more sensi-tive but captured only 47% of cases overall and 74.9% of theseptic shock cases [10]. This disconnect makes it difficult tobenchmark outcomes, improve treatment strategies and trans-late results of clinical trials to bedside care.

The SIRS–septic shock continuum is frequently used as a tri-age and capture tool for infected patients and has formed thebasis for the inclusion criteria of numerous sepsis trials [3,11,12].

This is intuitive since three of the SIRS criteria are core vitalsigns, obtained during triage or continuously at the bedside inmonitored patients. This is the inherent appeal of the SIRSconcept. Despite this, the sensitivity and specificity of theSIRS–septic shock continuum have never been clearlydelineated and have been challenged.

To understand the origin of the SIRS–septic shock contin-uum, one must go back to the failed immunomodulatory sepsistrials of the 1980s and the seminal work of the late RogerBone. ‘Sepsis syndrome,’ defined as, ‘a systemic response to asuspected or documented infection and at least one organ dys-function,’ was first described by Bone and colleagues from theMethylprednisolone Severe Sepsis Study Group in a 1989 posthoc analysis of the control group of the high-dose

Table 1. The sepsis continuum.

SIRS Sepsis Severe sepsis Septic shock Cryptic shock

Two or more

SIRS criteria

Two or more SIRS

criteria

Two or more

SIRS criteria

Two or more

SIRS criteria

Two or more

SIRS criteria

Temperature >100.4˚F

or <96.8˚F

(>38.0˚C or <36.0˚C)

Source of infection:

presumed or

documented

infectious focus

Source of infection Source of infection Source of infection

Tachycardia: heart

rate >90 b.p.m.

Infiltrate on chest

radiograph in patient

with signs and

symptoms consistent

with pneumonia

Acute organ

dysfunction: signs

of microvascular

compromise and

poor perfusion

Acute organ

dysfunction

Acute organ

dysfunction

Tachypnea: respiratory

rate >20 breaths

per minute

Infected fluid from a

normally sterile

site including

cerebrospinal fluid,

joint fluid and blood

Acute encephalopathy,

presenting as altered

mental status

Persistent hypotension:

systolic blood pressure

<90 mmHg or mean

arterial blood pressure

<65 mmHg or a SBP

reduction of >40 mmHg

from baseline despite

adequate fluid resuscitation

(20–30 cc bolus over 30 min)

Cryptic shock defined as

an elevated serum lactate

levels (>4 mmol/l) despite

being normotensive

or hypertensive

White blood cell

count >12,000 /mm3,

<4,000/mm3,

or >10%

immature cells

Urinanalysis and

microscopy consistent

with infection

Renal dysfunction,

presenting as

oliguria

Recognition that

inadequate oxygen

delivery to meet oxygen

consumption needs can

occur in patients who

are hypertensive,

normotensive or

hypotensive

Positive blood cultures Cardiac dysfunction,

presenting as hypotension

or myocardial depression

Obvious cellulitis Pulmonary dysfunction,

presenting as severe hypoxia

Purulent fluid drained

from abnormal

collection

Tissue-level hypoperfusion,

presenting as an elevated

serum lactate level

SIRS: Systemic inflammatory response syndrome.

Editorial Gaieski & Goyal

868 Expert Rev. Anti Infect. Ther. 11(9), (2013)

methylprednisolone trial [13]. As they stated, ‘the purpose ofour study was to define a syndrome that could be distinguishedon the basis of readily available, non-invasive clinical criteria atan earlier stage of deterioration than that previously describedin the literature. By doing so we hoped to define a point atwhich therapeutic interventions may be instituted with thegreatest likelihood for preventing the disastrous sequelae of thesepsis syndrome: namely septic shock and the acute respiratorydistress syndrome’ [13]. Of the 191 patients examined, 45%were bacteremic, 36% were in septic shock at ICU admission(mortality: 27.5%) and 23% more developed shock afteradmission (mortality: 43.2%).

It is fascinating that these post hoc findings from the controlgroup of a negative study became the foundation of the recom-mendations of the 1991 ACCP/SCCM consensus conferenceconvened with ‘the goal of agreeing on a set of definitions thatcould be applied to patients with sepsis and its sequelae’ [14].A few months prior to the conference, Bone published a per-suasive editorial, ‘Let’s agree on terminology: Definitions ofsepsis’ [15]. He defined sepsis as a suspected infection accompa-nied by the body’s systemic response to that infection; hedefined the sepsis syndrome as sepsis plus signs of organdysfunction.

Disagreement with these definitions was expressed in accom-panying editorials by Sprung and Sibbald [16,17]. Dr Sprung wasthe lead investigator of another multicenter high-dose steroidsfor severe sepsis trial, which also yielded negative results [18].He argued that the sepsis syndrome should be more broadlydefined to include patients with sepsis regardless of the signs oforgan dysfunction, and for gradations of septic shock based uponblood pressure, lactate and inotropic requirements [16]. The sec-ond editorial, by Sibbald, emphasized that Dr Bone’s definitionswere imprecise and would not ‘reduce the existing confusion thatsurrounds both clinical and investigative practice in critically illpatients,’ arguing: ‘the central concept that should underlie aclarification of the terms ‘infection’ and ‘sepsis’ is the discrimina-tion between phenomena that reflect effects of the microorgan-ism and those phenomena that reflect the response of thehost’ [17]. Echoing Osler’s observations from decades earlier, Sib-bald argued that sepsis is the host’s response to an insult, themost common of which is infection. Thus, sepsis (or the septicresponse) could be produced by pneumonia, pancreatitis, majorburns, trauma or other serious systemic insults.

Against this confusing background, the 1991 ACCP/SCCMconsensus conference had two proposed goals:

1. To ‘improve [the] ability to make early bedside detection ofthe disease possible and thus allow early therapeutic inter-vention’ and

2. The ‘standardization of research protocols’ [14].

Central to the consensus statement, based primarily onexpert opinion, was the newly coined term SIRS–the body’sinflammatory response to serious insults including infection.The only evidence the authors provided supporting the SIRSconcept was an analysis of 519 sepsis admissions to an ICU,

demonstrating that the new definition identified 96.9% of thepatients whereas the ‘sepsis syndrome’ definitions only captured55%. However, since the patients were already admitted to anICU with the diagnosis of sepsis, this evidence tells us nothingabout the previously stated goals – improving the ability tomake early bedside diagnosis and hasten implementation oftherapeutics. Labeling already differentiated ICU patients isvery different than sorting, or triaging, undifferentiated patientsin the ED or on hospital wards.

Since its publication, the 1992 SIRS–septic shock continuumhas been studied to assess its clinical relevance, used as the basisfor enrollment in clinical trials and criticized by sepsis experts.Rangel-Frausto et al. studied the epidemiology of the SIRS–septic shock continuum on general hospital wards and ICUs atan academic medical center [19]. They found that 68% ofpatients admitted met SIRS criteria; of these, 26% developedsepsis, 18% severe sepsis and 4% septic shock. They noted astepwise increase in mortality as patients moved along theSIRS–sepsis–severe sepsis–septic shock continuum: 7, 16,20 and 46%, respectively. The landmark 2001 study by Rivers,‘Early goal-directed therapy in the treatment of severe sepsisand septic shock,’ incorporated the SIRS criteria and 1991 sep-sis definitions into its inclusion criteria [4]. Patients were eligiblefor enrollment if they had: two or more SIRS criteria at triage;a presumed or documented source of infection; and either alactate ‡4 mmol/l or a systolic blood pressure not greater than90 mmHg after fluid challenge. The SIRS–septic shock contin-uum was also questioned by many. For example, in 1997 Jean-Louis Vincent [20] published an editorial, ‘Dear SIRS, I’m sorryto say that I don’t like you’. He argued that the addition ofthe SIRS concept to already existing terminology only obfus-cated an already murky situation. He argued that SIRS is ‘toosensitive, but is not specific,’ and that SIRS does not reflectpathophysiology: ‘We all have SIRS regularly. When we jog, orrun after the bus, we have tachycardia and tachypnea’ [20].

In 2001, the International Sepsis Definitions Conference wasconvened to address three goals:

1. Evaluation of the strengths and weaknesses of the 1991definitions;

2. Identify ways to improve these definitions and3. Identify ‘methodologies for increasing the accuracy, reliabil-

ity, and/or clinical utility of the diagnosis of sepsis.’

Asserting not only that SIRS is ‘too non-specific to be of util-ity in diagnosing a cause for the syndrome,’ and too sensitive asa screening tool [21], the 2001 International Sepsis Definitionsauthors added a list of ‘possible signs of systemic inflammationin response to infection’ including altered mental status; hyper-glycemia in the absence of diabetes; acute oliguria; anddecreased capillary refill. This was an attempt to incorporate theclinician’s gestalt that ‘the patient looks septic’ into the triage ofpatients with infection [21]. The benefit of this approach is theability to include patients excluded by the prior definition; theweakness is increased subjectivity, further confusing attempts tobenchmark outcomes and estimate incidence.

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In 2006, Shapiro provided evidence that the SIRS–septicshock continuum is not sufficiently sensitive to capture enoughpatients with suspected infection presenting to the ED [6]. In acohort of 3,102 patients, suspected infections without SIRSwere present in 45%; sepsis in 29%; severe sepsis in 24%; andseptic shock in 1.3%. There was no difference in the mortalitybetween patients admitted with suspected infection withoutSIRS versus those with sepsis. Mortality only increased whenpatients had organ dysfunction. Interestingly, 34% of patientswith severe sepsis and 24% of those with septic shock did notmeet SIRS criteria! Just as there are patients with SIRS andinfection who are no sicker than those with infection but noSIRS, there are critically ill patients with organ dysfunction butno SIRS. Alas, what is the utility of SIRS after all?

Where does this leave us? Back at the drawing board. Backat triage. Searching for ways to rapidly identify and risk stratifypatients with an inflammatory response secondary to infection–exploring the utility of point-of-care biomarkers, real-time tri-age-based sepsis scoring systems, personalized genetic andinflammatory profiles and rapid bacterial assays. To date, serumlactate is the best studied early detection technique. Multiplestudies have demonstrated an association between elevated lac-tate levels and outcomes in severe sepsis patients. For example,Mikkelsen et al. demonstrated a stepwise increase in mortalityas serum lactate levels increased in severe sepsis patients admit-ted to the hospital from the ED [22]. This increase in mortalitywas independent of hypotension. Rapid measurement of serumlactate has been incorporated into many ED and hospital-based sepsis screening tools and this simple technique can sig-nificantly improve capture of critically ill patients.

Identification of patients with severe sepsis appears to beimproving, treatment seems to be beginning earlier and mortal-ity seems to be decreasing. Education initiatives, such as theSurviving Sepsis Campaign, have increased awareness, demon-strating a 2-year decline in 28-day mortality from 37 to30.8%. Compliance with the initial 6-h bundle increased from

10.9 to 31.3% during the same period after initiation of theSSC guidelines. Bundled care of the septic patient promptsproviders to employ quantitative resuscitation and emphasizestime-sensitive critical interventions such as early antimicrobialadministration and aggressive volume resuscitation.

More research is necessary to confirm that the use of bundlesdirectly lead to improved outcomes. Gaieski and colleaguesrecent publication, ‘Benchmarking the Incidence of Severe Sep-sis in the United States,’ questions some of these findings.Regardless of the capture technique used, they demonstratedtwo significant findings: the annual increase in severe sepsiscases was about 13%; mortality was steadily decreasing by 2%per year. This raises the question ‘Is care improving?’ or areless sick patients now being categorized as severe sepsis? Wheredo we stand in our search for objective definitions of severesepsis among the winds of doctrines and wild theories?

Objective principles must be embraced in the next itera-tion of sepsis definitions. Perhaps, it is time to hold anotherSepsis Definitions Conference, including experts from theprehospital setting, Emergency Medicine and inpatient spe-cialties to review current knowledge, codify understanding,and develop new working definitions relevant to the rapididentification and treatment of undifferentiated patients whopotentially have severe infections. Only through further coop-eration will we be able to find a fixed aim and no longer becarried away by winds of doctrines and wild theories that dis-tract clinicians and researchers from the true burden ofsevere sepsis.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript. This

includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

References

1 Osler W. The study of the Fevers of the

South. JAMA 21, 999–1004 (1896).

2 Osler W. The evolution of modern

medicine. (1904).

3 Otero RM, Nguyen HB, Huang DT et al.Early goal-directed therapy in severe sepsis

and septic shock revisited: concepts,

controversies, and contemporary findings.

Chest 130 (5), 1579–1595 (2006).

4 Rivers E, Nguyen B, Havstad S et al.; EarlyGoal-Directed Therapy Collaborative G.

Early goal-directed therapy in the treatment

of severe sepsis and septic shock. New Engl.J Med. 345 (19), 1368–1377 (2001).

5 Kumar A, Roberts D, Wood KE et al.Duration of hypotension before initiation of

effective antimicrobial therapy is the critical

determinant of survival in human septic

shock. Crit. Care Med. 34(6), 1589–1596(2006).

6 Shapiro N, Howell MD, Bates DW,

Angus DC, Ngo L, Talmor D. The

association of sepsis syndrome and organ

dysfunction with mortality in emergency

department patients with suspected

infection. [see comment]. Ann. Emerg. Med.48(5), 583–590.

7 Slade E, Tamber PS, Vincent J-L. The

surviving sepsis campaign: raising awareness

to reduce mortality. Crit. Care 7(1), 1(2003).

8 Angus DC, Linde-Zwirble WT, Lidicker J

et al. Epidemiology of severe sepsis in the

United States: analysis of incidence,

outcome, and associated costs of care. Crit.Care Med. 29(7), 1303–1310 (2001).

9 Gaieski DF, Edwards JM, Kallan MJ,

Carr BG. Benchmarking the incidence and

mortality of severe sepsis in the United

States. Crit. Care Med. 41(5), 1167–1174(2013).

10 Whittaker SA, Mikkelsen ME, Gaieski DF,

Koshy S, Kean C, Fuchs BD. Severe sepsis

cohorts derived from claims-based strategies

appear to be biased toward a more severely

ill patient population. Crit. Care Med.41(4), 945–953 (2013).

11 Jones AE, Shapiro NI, Trzeciak S,

Arnold RC, Claremont HA, Kline JA.

Lactate clearance vs central venous oxygen

saturation as goals of early sepsis therapy.

JAMA 308(8), 739–746 (2010).

12 Schortgen F, Clabault K, Katsahian S et al.Fever control using external cooling in

septic shock: a randomized controlled trial.

Editorial Gaieski & Goyal

870 Expert Rev. Anti Infect. Ther. 11(9), (2013)

Am. J. Respir. Crit. Care Med. 185(10),1088–1095 (2012).

13 Bone RC, Fisher CJ Jr, Clemmer TP,

Slotman GJ, Metz CA, Balk RA;

Methylprednisolone Severe Sepsis Study

Group. Sepsis syndrome: a valid clinical

entity. Crit. Care Med. 17(5), 389–393(1989).

14 Bone RC, Balk RA, Cerra FB et al.Definitions for sepsis and organ failure and

guidelines for the use of innovative therapies

in sepsis. The ACCP/SCCM Consensus

Conference Committee. American College

of Chest Physicians/Society of Critical Care

Medicine. Chest 101(6), 1644–1655 (1992).

15 Bone RC. Let’s agree on terminology:

definitions of sepsis [see comment]. Crit.Care Med. 19(7), 973–976 (1991).

16 Sibbald WJ, Marshall J, Christou N et al.‘Sepsis’ – clarity of existing terminology ...

or more confusion? Crit. Care Med. 19(8),996–998 (1991).

17 Sprung CL. Definitions of sepsis–have we

reached a consensus? Crit. Care Med. 19(7),849–851 (1991).

18 The Veterans Administration Systemic

Sepsis Cooperative Study Group. Effect of

high-dose glucocorticoid therapy on

mortality in patients with clinical signs of

systemic sepsis. New Engl. J. Med. 317(11),659–665 (1987).

19 Rangel-Frausto MS, Pittet D, Costigan M,

Hwang T, Davis CS, Wenzel RP. The

natural history of the systemic inflammatory

response syndrome (SIRS). A prospective

study. JAMA 273(2), 117–123 (1995).

20 Vincent JL. Dear SIRS, I’m sorry to say

that I don’t like you. Crit. Care Med. 25(2),372–374 (1997).

21 Levy MM, Fink MP, Marshall JC et al.2001 SCCM/ESICM/ACCP/ATS/SIS

International Sepsis Definitions Conference.

Intensive Care Med. 29(4), 530–538 (2003).

22 Mikkelsen ME, Miltiades AN, Gaieski DF

et al. Serum lactate is associated with

mortality in severe sepsis independent of

organ failure and shock. Crit. Care Med.37(5), 1670–1677 (2009).

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www.expert-reviews.com 871