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Sepsis-3Michelle Carney, MD

October 2018

No FinancialDisclosures

(One Personal Disclosure: I am an ID physician)

Objectives

• Contrast new with old definitions of sepsis and septic shock

• Apply qSOFA and SOFA

• Highlight some management strategies from Surviving Sepsis Campaign (SSC) 2016

• Understand some of the controversy surrounding Sepsis 3 and SSC 2016

Bone et al., Chest 1992; 101:1644

The Burden of Sepsis in the U.S. is High

• #1 cause of death in the non coronary ICU1

• May contribute to 30-50% of hospital deaths2

• Most expensive condition treated in hospitals3

• Survivors also at high risk for recurrent sepsis, readmission, cognitive and functional impairment4

• There is no gold standard diagnostic test for sepsis-sepsis is a complex, heterogeneous syndrome

• Most studies are observational and not risk adjusted and subject to bias• Reporting national mortality without severity and covariate adjustment

can lead to misleading results• Early recognition and timely evidenced-based interventions probably

reduces mortality. The Surviving Sepsis Campaign has done a lot of good by focusing attention on early diagnosis and optimal treatment

1. Minino et al, NCHS Data Brief (2012)2. Liu et al, JAMA (2014)3. Torio et al, HCUP Statistical Brief #160 (2013)4. Winters et al, Crit Care Med (2010)

History of Sepsis Definitions:“Sepsis-1”

“Sepsis represents the systemic inflammatory response to the presence of infection”

• SIRS = ≥2 of: Temperature >38.0 or <36.0; Heart Rate >90 bpm; Respiratory Rate >20/min; WBC >12k, <4k, or >10% bands

• Sepsis = Infection + SIRS

• Severe Sepsis = Sepsis + Organ Dysfunction

• Septic Shock = Sepsis + Refractory Hypotension (despite fluids)

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“SEPSIS-2” - 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS

• Expanded list of possible diagnostic criteria, but otherwise no significant change to this framework

Crit Care Med 2003;31:1250-56

Am J Resp Crit Care Med. 2015:192(8):958-964

-Univ Chicago study-Ward pts, 5 hospitals,

11/08-1/13269,951 pts

-47% met 2 SIRS-screening ward pts for SIRS is impractical

Why a New Definition?

• SIRS criteria are problematic:• Nonspecific for infection/sepsis-poor specificity

• May miss 1 in 8 patients with serious infection + organ dysfunction1

• Sepsis = dysregulated host response to infection, but SIRS is actually physiologic

➢Organ dysfunction is key

• Confusing nomenclature: “sepsis” and “severe sepsis” used interchangeably

• Unclear definition for “organ dysfunction”

1. New Engl J Med 2015; 372:1629-1638

JAMA.2016;315(8)Editorial: "New Definitions

...but with Much Still to Be Done

Pathobiology of Sepsis:Self destruction

The consequence of unbalanced pro- and anti-inflammatory response

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Conceptual Changes

“Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection”

“Septic shock is a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities

are associated with a greater risk of mortality than with sepsis alone”

→ SIRS criteria removed from definition→“Severe Sepsis” removed from definition

(replaced by “Sepsis”)

The Third International Consensus Development of Definition and Clinical Criteria

• Sepsis and Septic Shock definitions should reflect pathobiology, allow consistency for epidemiologic and clinical studies and facilitate more timely management

• Shankar-Hari et al used task force of 19• systematically reviewed 44 sepsis studies (166,479 pts) to identify various

constellations of clinical criteria and mortality associated• Described variability of that review then found consensus via a Delphi study

(3 surveys/discussions)• then used cohort studies of various EHR data bases to test (mortality as

outcome measure): n=28,150 from Surviving Sepsis Campaign 2005–2010; n=1,309,025 Univ Pitt Med Ctr 2010-2012; n= 1,847,165 Kaiser Permanente Northern California 2009–2013

The Third International consensusAssessment of Clinical Criteria

• Seymour et al used EHR of 4,885,558 encounters from 177 hospitals to validate criteria used in the definitions

• Mortality and >3d ICU stay used as outcome criteria

• Compared SIRS, SOFA, qSOFA and LODS +/- lactic acid in ICU and non-ICU cohorts

• CONCLUDED:• Increased SOFA by 2 points in ICU patients predicted

mortality >10%• qSOFA of 2 in non-ICU patients predicted mortality >10%• In post hoc analysis, adding lactate >2 in qSOFA 1 gave

same mortality risk as qSOFA of 2

SEPSIS-3

• Singer et al article outlines the consensus definitions agreed upon by the 19 member expert panel combining the Seymour "Assessment" and Shankar-Hari "Development"

• Recognizes sepsis as a syndrome without a validated criterion standard diagnostic test; defines sepsis by describing what it "is"

• Lay terms: "Sepsis is a life-threatening condition that arises when the body's response to infection injures its own tissues and organs"

• Acknowledges that culture-positive "sepsis" is only observed in 30% to 40%

• Calls the updated definitions a "work in progress"

Sepsis Clinical Criteria

• Sepsis• Suspected or documented infection and an acute increase > 2 SOFA points or

a qSOFA of > 2

• Septic Shock• Sepsis with vasopressor therapy needed to elevate MAP > 65 mmHg and

lactate > 2 mmol/L after adequate hydration

Sepsis-3: Operational Clinical Criteria

• Sepsis = Infection + increase in SOFA score by ≥2 points from baseline

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qSOFA-"HAT"

• Hypotension-SBP<100

• Altered mental status-GCS < 15 (GCS 15 requires

a)spontaneous eye opening

b)accurate orientation person/place/ time

c)appropriate motor response to commands

• Tachypnea-RR>22

Sepsis-3: Operational Clinical CriteriaThird International Consensus Definitions

SEPSIS

• life threatening organ dysfunction due to dysregulated host response to infection

• Infected non-ICU with 2/3 qSOFA *

• Infected ICU with SOFA increase >2

• Lactate not additive

• In-hospital mortality >10%; ICU stay > 3 days

Third International Consensus Definitions

• SEPTIC SHOCK

• Subset of sepsis in which PPOFOUND circulatory, cellular and metabolic abnormalities

• Despite volume replacement, require vasopressors for MAP > 65

• and lactate >2

• In hospital mortality >40%

Sepsis-3: Criticisms and Limitations

• Concern that focus on qSOFA / organ dysfunction may delay early recognition and treatment of severe infection-not a screening tool• Will these changes reverse decades of quality improvement efforts with old

definitions?

• SOFA mainly developed as a research tool rather than for clinical use• Not easy to memorize or readily available at the bedside

• Definitions are not harmonized with SEP-1 CMS reporting measure• creates confusion

Reasons for Caution: Deficiencies in Surveillance and Diagnosis

• Current surveillance using ICD-9/ICD-10 codes are less reliable because:

▪ Rising awareness of sepsis

▪ Financial pressures to code for greater patient complexity (e.g. MS-DRG system)

• Compounded by subjectivity in sepsis diagnosis (“suspected infection,” attributing organ dysfunction to sepsis)

• 5 case vignettes of patients with suspected or confirmed infection and possible organ dysfunction distributed to 94 academic intensivists

➢ Respondents classified cases as SIRS alone, sepsis, severe sepsis, septic shock, or none of the above

Crit Care 2016; 20:89

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National Data: Hospitalizations with Infections Listed as Primary Diagnosis, 2003-2011

N Engl J Med 2014; 370:1673-1676

Annual Incidence of Objective Clinical Markers, 2003-2012

Clin Infect Dis 2015; 60:88-95

EHR-Based Clinical Surveillance

• Instead of claims data, can we track clinical indicators of sepsis using more consistent and uniform criteria?➢ Presumed infection (e.g. cultures, antibiotics) +

➢ Organ dysfunction (e.g., vasopressors, mechanical ventilation, changes in baseline laboratory values)

JAMA 2017;318:1241-1249

Goals:1. Create an objective sepsis surveillance definition based

on clinical data that can be applied across different EHR systems

2. Apply this definition to diverse hospitals from across the U.S. to generate credible estimates of current national sepsis burden and trends

Presumed Serious Infection• Blood cultures obtained +

• ≥4 Antibiotic Days (starting within +/-2 days of blood culture day)

Acute Organ Dysfunction (any within +/-2 days of blood culture day):

• Cardiovascular: Initiation of a vasopressor

• Respiratory: Initiation of invasive mechanical ventilation

• Renal: Doubling in serum creatinine or decrease by ≥50% of eGFR relative to

baseline (excluding patients with ESRD)

• Hepatic: Total bilirubin ≥ 2.0 mg/dL and increase by 100% from baseline

• Hematologic: Platelet count <100 cells/µL and ≥ 50% decline from baseline

(baseline must be ≥100 cells/µL)

• Perfusion: Serum lactate ≥ 2.0 mmol/L

Sepsis Clinical Surveillance Definition

Standardized rules implemented for calculating “baseline” laboratory values

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Distribution of Study Hospital Characteristics vs All US Hospitals Sepsis Clinical Characteristics, Incidence, and Outcomes in 2014

• 173,690 adult sepsis cases

→Overall 6% incidence

• 87% present-on-admission, 13% hospital-onset

• 55% admitted to ICU

• 17% had positive blood cultures

• 15% had septic shock (vasopressors + lactate ≥2)

• 15% died in-hospital• Higher mortality for hospital-onset sepsis (26%) vs sepsis

present-on-admission (14%)

Summary

• Sepsis is common: • ~ 6% of adult hospitalizations• ~ 1.7 million U.S. cases annually

• Sepsis is lethal: • >1 in 5 sepsis patients died or discharged to hospice• Present in >1/3 of all hospitalizations that culminated in death• Potentially contributes to ~270,000 U.S. deaths annually

• Sepsis trends have been fairly stable from 2009-2014:• Incidence rates stable (mild rise if including lactate criteria, likely due

to more testing)• Hospital-mortality rates have declined slightly, but no significant

change when considering discharge to hospice • Clinical data contrast with claims-based trends

• EHR-surveillance compares well with medical record reviews• Imperfect but better than claims-based methods

JAMA 2017;318:1241-1249

Surviving Sepsis Campaign 2016 Management Guidelines• An update of the 2012 based upon lit review/expert panel

• Old definitions of sepsis, severe sepsis, septic shock

• Working groups for five sections: hemodynamics, infection, adjunctive therapies, metabolic and ventilation made 93 recommendations

• Graded recommendations were voted upon by the panel

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate levels

2) Obtain blood cultures prior to administration of antibiotic

3) Administer broad spectrum antibiotics

4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) 65 mm Hg

6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)*

- Measure central venous oxygen saturation (ScvO2)*

7) Remeasure lactate if initial lactate was elevated

*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg, ScvO2 of 70%, and normalization of lactate.

CCM 2013; 41,2:580

2012SURVIVING

SEPSIS CAMPAIGN3 and 6 hour

BUNDLES

The CMS “SEP-1” Core Measure

• In October 2015, the Centers for Medicare and Medicaid Services began requiring hospitals to report compliance rates with the “SEP-1” sepsis core measure• Requires 3 and 6 hour bundles of care adapted from the Surviving Sepsis

Campaign Guidelines for patients diagnosed with severe sepsis / septic shock

• Many hospitals around the country are now devoting substantial resources to meeting and abstracting the measure

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Crit Care Med 2018; 46:1585-1591

Summary and Conclusions

• Most sepsis patients received care that was non-compliant with SEP-1 • Failure to measure lactates accounted for 40% of failures

• Cases that failed SEP-1 were very different than those that passed• More septic shock, hospital-onset sepsis, and vague symptoms

• Crude mortality rates were higher in cases that failed SEP-1, but there was no significant difference after adjusting for clinical characteristics

• Delays in appropriate antibiotics(> 3 hours) were associated with higher mortality rates but only accounted for 15% of SEP-1 failures

SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Management Cornerstones

• Initial Resuscitation

• Source Control

• Antibiotics

Initial resuscitation

• Early Goal Directed Therapy is out due to three 2014-2015 NEJM studies (ProCESS, ARISE and PROMISE) and a meta analysis (Intensive Care Medecine 4(9)1549-1560)

• Early recognition and prompt action is in:

•Adequate resuscitation

•Vasopressor support

•Early antibiotics

Adequate resuscitation-FLUIDS

Fluids–30 ml/Kg of IV crystalloid fluid; albumin may be used in

patients requiring large amts of fluid

Monitoring

Hemodynamic status (HR, BP, O2 sat, RR, temp, UO)

Target MAP of 65mmHg

Decreasing serum lactate (goal <2mmol/L)

Vasopressors

Norepinephrine is first line

• Goal is MAP 65mmHg

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Vasopressor Support

• Norepinephrine is recommended first line• Vasopressin added to norepinephrine (JAMA 2018 meta analysis of

23 trials) although no change in mortality, lower rate of A fib and possibly protective of arrhythmia

• Dobutamine may be initiated in patients with persistent hypoperfusion despite fluids and vasopressors

• Epinephrine may be added but is a second catecholamine

Clin Infect Dis 2018; 66:1631-1635

1. Distinguishing sepsis from noninfectious syndrome2. Time to initiation of empiric therapy3. Blood cultures and IV access catheters4. Combination and multidrug therapy5. Procalcitonin6. Pharmacokinetics/Pharmacodynamics7. Duration of therapy

IDSA's concerns with 2016 SSC 1/2

• Failure to acknowledge practical difficulties in diagnosis of sepsis citing a 2015 study in CCM w/40% ICU "sepsis" admissions without infection

• Rigid 1 hour initiation broad antibiotic to lead to over use/CMS std of care,etc vs proposal for sepsis equivallent of htn urgency and septic shock of htn emergency

• Unclear guidance regarding catheter removal

• Combination and Multidrug references are unclear; better guidance could have been given and some guidance is just incorrect

• Multidrug several days past clinical improvement

IDSA's concerns with 2016 SSC 2/2

• Multiple statements imply most with sepsis or septic shock harbor antimicrobial resistane pathogens and this is not the case

• Procalcitonin rises within 4-6 hours in invasive bacterial infection; this guideline does not specify how to best use

• Operationalization of optimizing pharmacokinetics/pharmacodynamics needs to be specified

• Infection prevention is not addressed

• Duration of therapy suggested is longer than necessary

• IDSA is disappointed disagreements could not be resolved prior to release

Surviving Sepsis Campaign 2018 Mandate

Treat first and then evaluate later Intensive Care Med 2018; 44:925-928Crit Care Med 2018; 46:997-1000

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The Surviving Sepsis Campaign Bundle:2018 update

Revision of the SSC bundles is that the 3-h and 6-h bundles have been combined into a single “hour-1 bundle” with the explicit intention of beginning resuscitation and management immediately.

The Surviving Sepsis Campaign Bundle:2018 update

* No mention of appropriate specimen collection except blood cultures**Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established or discontinued if a decision is made that the patient does not have infection

**

*

Inconvenient Truths• High rate of overdiagnosis

• Approach promotes excess antimicrobial use and increases unintended consequences• C difficile infections

• Acute kidney injury and other side effects (e.g. ↑ LFT, rash, hematologic)

• Missed culture opportunities (antibiotics administered before appropriate cultures obtained)

• Selection for MDROs

• Alteration of microbiome-dysbiosis

• Up to 40% of patients admitted to ICU with admitting diagnosis of sepsis did nothave an infection. (Crit Care Med 2015; 19:319)

• Cultures positive in only a minority of cases leading to diagnostic uncertainty which increases broad spectrum antimicrobial use and duration

Inconvenient Truths-2

• Time to antibiotics matters for septic shock, but evidence is less convincing for patients with possible sepsis without shock• Two recent studies confirmed association between delay in antimicrobial administration and

mortality in patients with septic shock but little or no association for patients without shock (N Engl J Med 2017; 376:2235-2244; Am J Respir Crit Care Med 2017; 196:856-863)

• Randomized trial of antibiotics administered in the ambulance versus administered in ED for patients with suspected sepsis found mortality was the same in both groups. More than 90% of patients enrolled in study had infection alone or sepsis without shock. (Lancet Respir Med 2018; 6:40-50)

• Rigid mandates can hinder clinicians’ judgment in evaluating individual patients

• Studies have demonstrated that recent antibiotic exposure increases the risk of sepsis, probably by alterations in the microbiome.(Clin Infect Dis 2017; 66:1004–12) Therefore, reducing unnecessary antibiotic use could reduce future sepsis burden.

JAMA Published online September 14, 2018

Raising Concerns About Sepsis-3 Definitions

• The Global Alliance for Infections in Surgery: 78 authors from around the world

• Biggest concern: no prospective validation in a generalizable population

• qSOFA not as diagnostic but rather as warning of poor outcome

• Continuum idea is helpful and should not be eliminated

• Distinguish screening tool from risk stratification tool—feel we still need a screening tool

World J Emerg Surg 13:6;2018

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Pulmonary Critical Care Community Blogs

• Online petition to retire SSC guidelines

• SSC guideline was originally sponsored by Eli Lily and Edwards Life Sciences

• Recommendations unsupported by good quality of evidence becoming standard of care

• "Bundling" elevates unhelpful elements

• 2018 update "1 hour bundle" is dangerous

• Becomes core measure or state mandate

• Eliminates thoughtfulness (wrt fluid overload, inappropriate abx)

• Over-treatment is likely

New Definitions...Much Still to Be Done

• Sepsis is a syndrome, not a specific disease—there is no sepsis trigger

• Infection cannot always be confirmed (despite PCR, MALDI-TOF, etc)

• Organ system dysfunction may not be infection (trauma, pancreatitis)

• Cellular dysfunction is heterogeneous

• Precision medicine using specific biomarkers (cell receptors, intracellular pathways, genomic alterations) are not yet possible

Editorial JAMA 315(8)2016

Where do we go from here?• Reassess the 1 hour bundle for sepsis without shock. Should the need to rapidly and

aggressively treat patients be determined by the severity of illness and certainty of diagnosis rather than applied to all patients?

• Integration of biomarkers and rapid/molecular testing

• Move to an objective clinical surveillance diagnosis for sepsis

• Develop a true predictive model to alert clinicians to patients at risk for progression especially not POA

• Can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?

• Research to determine the predictors of long-term morbidity and mortality and interventions to prevent long-term morbidity and mortality for patients who survive sepsis(societal $$$)

• Use risk adjustment to evaluate most effective interventions and outcomes

• What are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?

• What is the optimal fluid for sepsis resuscitation?

• What is time zero?

Modified Crit Care Med 2018; 46:1344-1356

Clin Infect Dis 2018; 67:1300-1302

Measurement

• Outcome oriented

• Risk adjusted

• Cost of measurement

• Unintended consequences

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Old

Antibiotics as miracles

(“No downside risk, so why not try?”)

New

Antibiotics: Good when used well, better when used

thoughtfully

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