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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
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Emergency Department Critical Care Volume Increases
> 50% of Severe Sepsis cases initially present to the ED
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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
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000
2001 2025 2050
Year
100,000
200,000
300,000
400,000
500,000
600,000
Severe Sepsis Cases
US Population
Se
psi
s C
ase
s
To
tal
US
Po
pu
lati
on
/1,0
00
Incidence projected to increase by 1.5% per year
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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.
AIDS* Colon BreastCancer§
CHF† Severe Sepsis‡
Ca
ses/
100
,00
0
0
50
100
150
200
250
300
Incidence of Severe Sepsis Mortality of Severe Sepsis
0
50,000
100,000
150,000
200,000
250,000
De
ath
s/Y
ea
r
AIDS* SevereSepsis‡
AMI†Breast Cancer§
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Why do you think that severe sepsis has not received
the same focus as these other common diseases?
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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
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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
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Surviving Sepsis
CampaignAdult and Pediatric
Evidence-based Studies
1. Early Detection2. Early Treatment
• Sepsis Resuscitation Bundle
3. Monitor reliability and outcomes
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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
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Where is the Gain?
A B
Lead Time to Diagnosis Delivery of Proper Treatment
Lead time to Diagnosis Delivery of Proper Treatment
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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.
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Dear SIRS, I don’t like you...
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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Biomarkers in Sepsis
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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
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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
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Journal for Healthcare Quality. 2014; 36(1): 52-61
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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
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THANK YOU