Early Management of Severe Sepsis( the role of biomarkers )

Frans JV PangalilaIntensivist

• every few seconds someone dies of sepsis across the globe and 20 000 000 - 30 000 000 people are affected every year

Do You Know – What has been reported by Global Sepsis Alliance ?

Sepsis is one of the most common but least recognized disease !!

Reducing Mortality in Severe Sepsis

Severe Sepsis Bundle Sepsis resuscitation bundle Sepsis management bundle

Sepsis Resuscitation Bundle : Rationale

Infectious insult-Sepsis

Inflammatory mediators

Hypovolemia

Vasodilatation

Myocardial depression

Cytopathic tissue hypoxia and

microcirculation impairment

Coagulation activity

Cardiovascular insufficiency

Global Tissue Hypoxia

Markers of the High Risk paients

Organ dysfunction

Cardiac output is not adequate to bring O2 delivery to meet O2 demand

• Lactate• Scvo2 (mixed vein)• Inflammatory markers - eosinophil, netrofil, CRP procalcitonin

“ Sepsis Resuscitation Bundle “( 3 → 7 Indicators )

1. measure lactate : if lactate > 4 mmol

2. obtain blood culture3. administration broad spectrum antibiotic within :

- 3 hours in ED- 1 hours in ICU

Hypotension or Lactate > 4 mmol

Indicators : 4 → 7

No Hypotension Indicators 1 → 3 : within 6

hours4. delivery of an initial of a 20 ml/kg of crystalloid (or colloid equivalent)5. Hypotension (+)→ vasopresor (+) maintain MAP > 65 mmhg→ if persistent hypotension + lactate > 4mmol

Indicators 6 , 76. insertion CVC : achieves CVP > 8 mmHg7. and achieves mixed vein > 70 %

If

Aerobic02 (+)

Anaerob

Lactate Metabolism

28-Days in Hospital Mortality risk stratified by Blood pressure and Lactate level

Vernon Ch et al.Critical Care Clinic(26) 2010

Mixed Vein Oxygen Saturation (Svo2)

Mixed Vein (Sv02)( 65 – 75% )

( < 65% )• DO2 ↓ : - PaO2 ↓ - Hb↓ - CO ↓• VO2 - stress/pain - hyperthermia - WOB ↑

( > 75%)• good responds to resuscitation• cytopathic hypoxia

J Inflammation 2010

ScvO2 Lactate Interpretation

↑ ↓ good response to resuscitation

↑ ↑ Shunt a Sepsis b or Cytopathic c

↓ ↓ well compensated low CO or low SaO2

↓ ↑ poor response to resuscitationa low capillary extraction

b inhibition of pyruvate dehydrogenase, low O2 utilizationc mitocondrial cytopathy, low O2 utilization

Assess adequacy of Hemodynamic Support by Keeping Monitor for Scvo2 and Lactate level

Vincent et al ICM 2006

Situation Today...death from the hospital superbugs could

double over the next five years, experts have warned !!!.....18 june 2004, BBC News

Wensel et al 2008

↑ microorganism resistant / superbugs

High Mortality Reaching 75% !!- How to Treat ? CID 2009

Situation Today

The Impact of MDR Pathogens

Infection with MDR is associated with negative health outcome

increase of morbidity and mortality length of ICU and Hospital stay healthcare cost

Few antibiotic choice remains highlights the need to optimize existing classes of antimicrobials through adequate – appropriate use and infection prevention

Population of patients not infected with

MDR

Subpopulation of patients infected

with MDRInfectioncolonization

Driven by Two main factors : antibiotic misused or overused by physician

- lack of confidence to diagnose infection - poor understanding of antibiotic pk/pd parameter

poor understanding of sensitivity patterns of the local community

Factors that influence the acquisition of a MDR infection

Another factors : severity of ilness Immune system age and comorbid conditions nurse patient ratio hand washing and barrier precautions health care workers compliance

(CHEST 2003)

“ Get it Right the First Time “

Axiom : its really important for the physician to appreciate - what they entertained for the first time !!....severe sepsis ?....high risk of MDR ?

Should be given : Antibiotic ??

Congestive Heart Failure Std III - alveolar edema Chest Trauma

If we given

overused antibiotic ? misused antibiotic ?

So , the Clinician need a Biomarker just to help to maked an Early Good Diagnosis

A Good Biomarker Would be improve clinical diagnosis of infections-sepsis early increase upon infection increase despite the presence of

immunosuppresive medication

guidence of antibiotic therapy prognostic marker and better corelation with

outcome

A large number of investigations on biomarkers

We focus on :

Neutrophil C-Reactive Protein

(CRP) Procalcitonin

ROC Curve of five markers infection markers for differentiating bacteremia from non bacteremia

CCR 2010

Conclusions :• absolute lymphopenia is a predictor bacteremia• NLCR even higher predicting bacteremia

Conclusion : maximum daily CRP variation > 4.1 mgdl from previous day plus anabsolute concentration > 8.7 mgdl associated with an 88% risk for acute infection

Note : A. Fast Response : CRP ratio day 4 < 0.4 B. Slow Response C. non Response : CRP ratio day 4 > 0.8 D. Biphasic Response day 4 decreased

< 0.8 after that increased > 0.8

Procalcitonin : “HORMOKINES” in Sepsis

-During a Bacterial Infection there is induction of CT-m RNA by LPS alone or in combination with IL-1beta/TNF alpha in all parenchymal tissues, and a general release of PCT, into the bloodstream

-During a Viral Infection IFN-gamma is being released, IFN-gamma inhibits IL- 1beta and by doing so inhibits the release of PCT

The Role of PCT : differentiate SIRS vs Sepsis

Infected pancreatitis with MODS

Infected pancreatitis without MODS

SAP

Ann Surg 2007

Typical Course of PCT Serum Level According to Patient Response to Antibiotic

Christ-Crain. Yearbook of Intensive Care and Emergency Medicine 2005

The Big Question :when to stop the antibiotic therapy ??

“ the expert said 8 days ““ patient is stable ““ patient is transferred to the ward ““ patient developed a rash ““ renal function is deteriorating ““ cultures came back negative “

Stopping Rules guided by PCT

- Christ-Crain . Am J Respir CCM 2006

Wow....p < 0.001, its really SAVE the patients, pockets

and planets

Priorities in the Early Management of Sepsis -Severe Sepsis

BacterialInvasion

Localised response• vasodilatation

• netrofil transmigration• hibernation

Systemic Pro-inflammatory state

Macrocirculatory satge (0-6 hrs)

Microcirculatorystage (6-24 hrs)

Mitochondrial stage ( > 24 hrs)

Cytokine leak

MOFMODS

Antibiotic Therapy

Goal Directed Haemodynamic Support

Natural Inhibitors of Haemcoagulation

Legend : maximum effectivity of intervention effectivity decreased

Elimination of trigger factors

maximizing tissue perfusion

minimizing iatrogenic injury of physiologic support