Sohil PothiawalaFAMS(EM), MRCSEd(A&E), M.Med(EM), MBBS

ConsultantDepartment of Emergency MedicineSingapore General Hospital

Making the diagnosis of Sepsis in the Emergency Department

Emergency Department Critical Care Volume Increases

> 50% of Severe Sepsis cases initially present to the ED

Severe Sepsis: A Significant Healthcare Challenge

Major cause of morbidity and mortality worldwide

Leading cause of death in non-coronary ICU

• Mortality rates associated with sepsis 30-50% for severe sepsis

50-60% for septic shock

Sepsis kills approximately 1,400 people worldwide every day

Future

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Comparison With Other Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000.‡Angus DC et al. Crit Care Med. 2001;29(7):1303-1310.

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Why do you think that severe sepsis has not received

the same focus as these other common diseases?

The Sepsis CascadeUnbalanced Immune Reaction

Coagulation and complement system

Procoagulant State

MicrovascularThrombosis

Mediators of Inflammation

Free Radical Damage

Vasodilatation CapillaryLeak

Endothelial damage

Tissue injury and Organ dysfunction

Except on few occasions,

the patient appears to die from

the body's response to infection

rather than from it."

Sir William Osler – 1904The Evolution of Modern Medicine

Surviving Sepsis

CampaignAdult and Pediatric

Evidence-based Studies

1. Early Detection2. Early Treatment

• Sepsis Resuscitation Bundle

3. Monitor reliability and outcomes

The Importance of Early Detection

Efforts to just treat recognized sepsis alone are incomplete

A critical aspect of mortality reduction in the Surviving Sepsis Campaign has been pushing practitioners to identify sepsis early. Levy MM, Dellinger RP, Townsend SR ,et al. The

Surviving Sepsis Campaign: Results Of An International Guideline-Based Performance Improvement Program Targeting Severe Sepsis. Crit Care Med. 2010 Feb;38(2):367-74.

It may well be that earlier recognition accounts for much of the signal in mortality reduction and partially explains sharply increasing incidence. Gaieski DF, Edwards JM, Kallan MJ, et al. Benchmarking

the Incidence and Mortality of Severe Sepsis in the United States. Crit Care Med. 2013 Feb

Where is the Gain?

A B

Lead Time to Diagnosis Delivery of Proper Treatment

Lead time to Diagnosis Delivery of Proper Treatment

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). 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.

Dear SIRS, I don’t like you...

Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis

Tachycardia

SBP<90mmHg

MAP < 70mmHg

(despite fluid)

Need for Vasopressors

Unexplained

metabolic acidosis

•Lactate > 1.5 times

upper normal

PaO2/FiO2 200 if lung

only dysfunction/site of

infection

PaO2/FiO2 250 with

other organ

dysfunction/lung not site

of infection UO <0.5 ml/kg per hr

(despite fluid)

Platelets <80,000/mm3

Decline in platelet

count of 50% over 3

days

Respiratory

Metabolic

Cardiovascular

Renal

Hematologic

Prognosis of emergency

department patients with

suspected infection and

intermediate lactate levels: a

systematic review.

Puskarich MA, et al

J Crit Care. 2014 Jun;29(3):334-9

Evidence of Lactate

Lactate Levels and Clearance

Lactate levels proportional to mortality and MODS

Lactate ≥ 4 associated with poorer outcomes

Clearance of lactate is associated with improved survival

Lactate clearance non-inferior to ScVO2 monitoring (Jones, JAMA, 2010)

Good means to screen for occult severe sepsis - occult sepsis is when the patient’s blood pressure and mental status are good, but the

patient is still at high risk of death

- 1 in 5 patients in the Rivers trial had MAP >100, half of these had high lactate

• Algorithms of care based on lactate clearance appear to work as well or better than other approaches

Biomarkers in Sepsis

Acute Phase Protein

Biomarkers

Cytokine Biomarkers

Coagulation Biomarkers

Soluble receptor,cell surface and other markers

CRP Il-6 aPTT sTREM-1

Procalcitonin Il-8 Protein C& S suPAR

Lipopolysaccharide-binding protein

Macrophage migration inhibitory factor

D-dimer,Fibrin,Thrombomodulin

Midregionalproadrenomedullin

Pentraxin High-mobility-group box 1

Plasminogenactivator inhibitor

PolymorphonuclearCD64 index

C Reactive Protein (CRP) Acute phase protein released 4-6hrs after stimulation

Greater availability

Performance to discriminate patients with and without sepsis is only moderate

Inferior compared to PCT, can’t predict prognosis or positivity of blood culture1

Some ability to correctly diagnose pts with severe sepsis in ED, but significantly inferior to PCT and IL-6

Elevated CRP correlates with increased risk of organ failure and death2

Levels decrease over 48 hrs with successful antimicrobial therapy

Increases even during minor infection and non-infectious states; unable to assess severity

1. Su L, et al. Value of sTREM-1, PCT and CRP serum levels as biomarkers for detecting bacteremia among sepsis patients

with new fever in ICU: a prospective cohort study BMC infect Dis 2012; 12:157

2. Lobo SM, et al. CRP levels correlate with mortality and organ failure in critically ill patients Chest 2003, 123:2043-49

Use of procalcitonin to reduce patients'

exposure to antibiotics in intensive care

units (PRORATA trial): a multicentre

randomised controlled trial

Lancet 2010 Feb 6;375(9713):463-74

High serum procalcitonin

concentrations in patients with sepsis

and infection.

Assicot M, et al. Lancet 1993 Feb

27;341(8844):515-8

Additional value of procalcitonin for

diagnosis of infection in patients with

fever at the emergency department.

de Kruif MD, et al. Crit Care Med. 2010

Feb;38(2):457-63.

Procalcitonin (PCT) Massive release in blood stream depends on sepsis severity

Levels increase 4-12 hrs of infection

Low specificity and sensitivity (<90%) to diagnose sepsis

Recent ED study found that PCT, IL-6 or CRP only moderately discriminate between infectious and non-infectious inflammation 1

Meta-analysis have suggested PCT cut-off 1.1ng/ml in sepsis and 4-45 ng/ml in septic shock 2,3

Recent guidelines of Inf Dis Soc of America and ACCC recommend PCT as adjunctive diagnostic marker

1. Tsalik EL at al. Discriminative valuie of inflamatory biomarkers for suspected sepsis. J Emerg Med 2012. 43:97-106

2. Wacker C, et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis

2013; 13: 426-35

3. Reinhart K, et al. Biomarkers in critically ill patients: procalcitonin. Crit Care Clin 2011; 27:253-63

Cytokines Il-6, IL-8

Reach peak within 2 hrs of infection

Studies comparing them to PCT and CRP found to be of inadequate discriminative value in sepsis 1,2

IL-6 levels decrease when infection is controlled and is predictive of survival 3

Limited value as induced by numerous non-infectious diseases

Role needs to be established with bigger studies

1. Harbarth S, et al. Diagnostic value of PCT, IL-6 and IL-8 in critically ill patients admitted with suspected sepsis. Am J Resp Crit Care

2001. 164:396-402

2. Tsalik EL at al. Discriminative valuie of inflamatory biomarkers for suspected sepsis. J Emerg Med 2012. 43:97-106

3. Tschaikowsky K, et al. predictive value of PCT, IL-6 and CRP for survival in postoperative patients with severe sepsis. J Crit care 2011;

26:54-64

sTREM-1 Soluble Triggering Receptor expressed on myeloid

cells-1

Released by activated phagocytes during sepsis

Moderate diagnostic accuracy for differentiating sepsis from SIRS

Non-inferior to TNF-a, IL-6, PCT and CRP 1,2

Present in other inflammatory diseases without infection

Requires larger studies

1. Barati M, et al. sTREM-1and the diagnosis of sepsis. J Crit Care 2010; 25:362.e1-362.e6

2. Latour-Perez J, et al. Diagnostic accuracy of sTREM-1 to identify infection in critically ill patients with SIRS. Clin

Biochem 2010; 43:720-24

suPAR Soluble Urokinase-type Plasminogen Activator

Expressed on neutrophils, lymphocytes, monocytes/macrophages

Little value as a single marker to detect CAP in patients with SIRS 1

General marker of inflammation and hence diagnostic value is low

May have some value for outcome predictions and monitoring response to treatment - Higher suPAR levels associated with increased mortality 2

1. Kofoed K, et al. Use of CRP, PCT, neutrophils, macrophage migration inhibitory factor, suPAR and sTREM-1 in combination to

diagnose infections: a prospective study. Crit Care 2007; 11:R38

2. Backes Y, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic

review. Intensive Care Med. 2012 Sep;38(9):1418-28

Multi-Marker Approach Combination of 3-6 pro-inflammatory markers more

accurately identified bacterial infection 1

Panel of 3 biomarkers best predicted onset of severe sepsis in ED 2

- No traditional markers

- Antagonist of IL-1 receptor (IL-1ra) : anti-inflamatory

- Protein C : coagulation

- Neutrophil Gelatinase associated Lipocalcin (NGAL): organ injury

Combination increases sensitivity and specificity

Opportunities for research for the right combination and cost-effectiveness

1. Kofoed K, et al. Use of CRP, PCT, neutrophils, macrophage migration inhibitory factor, suPAR and sTREM-1 in combination

to diagnose infections: a prospective study. Crit Care 2007; 11:R38

2. Shapiro NI, et al. A prospective multicenter derivation of a biomarker panel to assess the risk of organ dysfunction, shock,

and deth in emergency department patients with suspected sepsis. Crit Care Med 2009; 37:96-104

Biomarkers in Sepsis

Multiplex PCR-Based Pathogen Detection

Practical value of BC is impaired by delay in time to results and its positive in approx 30% patients 1

No role in immediate treatment decision

PCR detects specific sequences of bacterial and fungal rRNA2

1. Calandra T, et al. International sepsis forum consensus conference on definition of infection in ICU. Crit Care Med. 2005;

33:1538-48

2. Pletz MW, et al. Will PCR-based diagnostics improve outcomes in septic patients? A clinical view. Intv care med 2011; 37:1069-76

2. Pletz MW, et al. Will PCR-based diagnostics improve outcomes in septic patients? A clinical view. Intv care med 2011; 37:1069-73. Bloos F, et al. A multicenter trial to compare blood culture with PCR in severe human sepsis. Int care Med 2010; 36:241-7

Results theoretically available in 6-8 hrs

Positive PCR is good to rule in infection but sensitivity is too low to rule out

It has twice as many positive results than BC, but still leaves more than half of septic patients with a negative PCR3

Can detect only those pathogens covered by the target list of assay

Recommended as an add-on to conventional culture-based methods, but cannot replace BC2

Journal for Healthcare Quality. 2014; 36(1): 52-61

Conclusion

Early diagnosis is the key

Clinical examination + biomarkers + PCR aid in early detection

Key ED interventions improve sepsis care

Potential impact on patient outcomes

Initiation of early treatment using Sepsis Resuscitation Bundles

THANK YOU