SEPSIS Kuliah Prof Herdiman (S1) Rev 17112011

Holistic Approach in Management of Sepsis

Herdiman T. Pohan

Tropical Medicine and Infectious Disease DivisionInternal Medicine Department

Medical Faculty University of Indonesia

SepsisSepsisHost’s reactionHost’s reaction to to systemic invading microbessystemic invading microbes involves a involves a

rapidlyrapidly amplifying amplifying inflammatoryinflammatory signals and signals and responsesresponses that may spread that may spread beyond the invaded tissuebeyond the invaded tissue..

When counterregulatory control mechanisms are When counterregulatory control mechanisms are overwhelmedoverwhelmed, , homeostasis may failhomeostasis may fail, and , and dysfunction dysfunction

of major organof major organ may supervene. may supervene.

FurtherFurther imbalance response related to imbalance response related to hypotension and hypotension and septic shock septic shock with with multiple organ dysfunctionmultiple organ dysfunction leads to leads to

increasing increasing deathsdeaths

P PredispositionI InfectionR ResponseO Organ Failure

31st International Educational and Scientific Symposiumof Society Critical Care Medicine, San Diego, 2002

Systemic Inflammatory Response Syndrome (SIRS)

Host response to Inflammation include 2 of:

1. Temp >38oC or <36oC2. Heart rate >90x/’3. Respiratory rate >20x/’ or PaCO2<32mmHg4. White blood cells count >12.000/mm3, < 4.000 or bands >10%

Bone et al. Chest 1992;101:1644

Sepsis : a Disease Continuum

Infection

SIRS

Sepsis

Severe Sepsis

Septic Shock

Bone et al. Chest 1992;101:1644

SepsisSIRS Severe Sepsis Septic ShockInfection

Chest 1992;101:1644

A clinical response arising from a nonspecific insult, with 2 of the following: T >38oC or

<36oC HR >90

beats/min RR >20/min WBC

>12,000/mm3 or <4,000/mm3 or >10% bands

Microorganism invading

sterile tissue

SIRS with a

presumed or

confirmed infectious process

Sepsis with organ failure

Vascular collapseRenalHemostasisLungLA

Refractoryhypotension

Updated Definition Sepsis

SIRS (systemic manifestations) + Infection (documented/ suspected)

Severe sepsis Sepsis + sepsis-induced organ dysfunction or tissue

hypoperfusion

Sepsis-induced hypotension a systolic BP(SBP) <90 mmHg or MAP <70 mmHg or SBP

>40 mmHg or <2 SD below normal for age in the absence of other cause of hypotension

Septic Shock Sepsis-induced hypotension persisting despite adequate fluid

resuscitation

Bone, et al. 1992 Chest 101:1644-1655Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Criteria of Organ Dysfunction Aterial hypotension (MAP<70)Aterial hypotension (MAP<70) SCVO2 >70%SCVO2 >70% CI>3.5 L/mt/m2CI>3.5 L/mt/m2 Arterial hypoxemia (PaO2/FiO2 <300)Arterial hypoxemia (PaO2/FiO2 <300) Acute oliguria (urine output<0.5ml/kg/h for at least 2 Acute oliguria (urine output<0.5ml/kg/h for at least 2

hours)hours) Creatinin increase Creatinin increase >>0.5mg/dL0.5mg/dL Coagulation abnormalites (INR >1.5 or aPTT > 60 sec)Coagulation abnormalites (INR >1.5 or aPTT > 60 sec) IleusIleus Thombocytopenia <100.000/uLThombocytopenia <100.000/uL Hyperbilirubinemia >4 mg?dLHyperbilirubinemia >4 mg?dL Hyperlactatemia >3 mmol/LHyperlactatemia >3 mmol/L Decrease capilary fillDecrease capilary fill

SCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definition Cofence,2001

Emergency Medicine 2010

Tissue Perfusion

Sepsis : a Complex Clinical Challenge

High mortality rate Heterogeneous patient population Unpredictable disease progression Unclear etiology and pathogenesis

Wheeler, Bernard. N Eng J Med. 1999;340:207

Endothelium

ProstaglandinsLeukotrienes

ProteasesOxidants

Activation and binding of

macrophage

Increased NO

NO

Vasodilation

Increasedactivity of iNOS

Sepsis

Transcription of immunomodulatory cytokines

(TNF-, interlukin-1,interleukin-10)

Binding ofPeptidoglycan of

Gram-positive bacilliCD 14

TLR-2

TLR-4

Binding ofLipopolysacharida ofGram-negative bacilli

Release of NF-kand transfer 10

nucleus

NF-k

Russel, N Eng J Med 355(16):1699, Nov 2006

Clinical conditions associated with sepsis

Gastrointestinal Liver Gallbladder Colon Intraabdominal abscess Intestinal obstruction Intraabdominal instrumentationGenitourinary Acute pyelonephritis Renal abscess Renal calculi Urinary tract obstruction Prostatic abscess InstrumentationPelvic Pelvic abscess, peritonitis

Intravascular Central iv line Infected prostetic device Septic thrombophlebitisLower respiratory tract Community acquired pneumonia Nosocomial pneumonia Empyema Lung abscessCardiovascular Acute bacterial endocarditis Myocardial abscessCentral nervous system Bacterial meningitis Brain abscess Perimeningeal infection

Cunha B. In : Conn Current Therapy 2003

Conditions not associated with sepsis

Gastrointestinal Esophagitis Gastritis Pancreatitis Small bowel disorders GIT bleedingGenitourinary Urethritis Cystitis Cervicitis Vaginitis Catheter associated bacteri- uria in immunocompetentUpper respiratory tract Pharingitis Sinusitis Bronchitis

Lower respiratory tract Community acquired pneumonia in immunocompetent Acute respiratory distress syndr Pulmonary hemorrhage Pulmonary vasculitisCardiovascular Subacute bacterial endocarditis Myocarditis Pericarditis Cardiac tamponadeSkin and soft tissue Septic arthritis Acute/chronic osteomyelitis Uncomplicated wound infection Decubitus ulcers


(A) INFECTIOUS AGENT (S) : toxin & other

virulence factors

(B) HOST DEFENSES : natural barriers, humoral & cell-mediated immunity

(C) UNFAVORABLE HOST FACTORSIncreasing ageBreakdown of barriersAcquired immunodeficiency syndromeDiabetes melitusCancerAspleniaEnd-organ diseaseNeutropenia, lymphopeniaChemotherapy, steroids & otherImmunosuppressive agents

(D) MANAGEMENTResuscitative and supportive

measuresAppropriate and timely antibioticsTargeted diagnosticsCloser monitoring (triaging)Source control or anatomic repair :

surgery, interventional radiology, etc.Reduction of immunosuppressionAdjunctive medical therapy

(e.g. IVIG, activated protein C, etc.)

Death Health

Mild disease

Moderate disease

Severe disease

Nicolasora N, Kaul DR. Infectious disease emergencies. Med Clin N Am 92. 2008

Why Mortality Remains High??

Therapeutic Goals in Management of Sepsis

Threat the underlying infections Preserve vital organ perfusion Maintain tissue oxygenation Modified the maladaptive inflammation process Avoid complication

Lynn WA. In: Amstrong D. Cohen J. Infectious Diseases, 1999

General Concept in Management of Sepsis

Elimination source of infection Antimicrobial treatment Supportive treatment Modification the maladaptive immune response

Sessler CN, Shepherd W. Curr Opin in Crit Care 2002;8:465-72

Clinicians

InfectiousDiseases

Nephrologist

Hematologist

IntensiveCare

Surgeons

Management of Sepsis in Hospital Settingand Intensive Care Units

Surviving Sepsis Campaign: International Guidelines for

Management of Severe Sepsis and Septic Shock, 2008

A.A. Initial Initial rresuscitationesuscitationB.B. DiagnosisDiagnosisC.C. Antibiotic therapyAntibiotic therapyD.D. Source Source ccontrolontrolE.E. Fluid Fluid ttherapyherapyF.F. VasopressorsVasopressorsG.G. Inotropic Inotropic ttherapyherapyH.H. Steroids Steroids I.I. Recombinant Recombinant hhuman uman aactivated ctivated pprotein Crotein CJ.J. Blood Blood pproduct roduct aadministrationdministration

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Supportive Therapy

A. Initial Resucitation

In case of severe sepsis, hypotension or shock

Early in 6 hour period

Fluid therapy, oxygenization, vasopresor Transfusion if needed

Monitoring

Rivers E, Nguyen B, Havstad S, et al. N Eng J Med 2001;345:1368-77

Monitoring in Sepsis

Monitoring is essential in unstable conditions (severe sepsis or shock)

Clinical examination and assessment can’t be subtitued by invasive monitoring

Minimal requirement include blood pressure, continuous cardiac monitoring, central venous pressure, rapid blood gas analysis

Lynn WA. In: Amstrong D, Cohen J. Infectious Diseases, 1999

SepsisSIRS Severe Sepsis Septic ShockInfection

Early Goal Directed Therapy

EARLY GOAL DIRECT THERAPY (EGDT)

Early Goal-Directed Therapy (EGDT): involves adjustments of cardiac preload, afterload, and contractility to balance O2 delivery with O2 demand: Fluids, Blood, and Inotropes

Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368.

CVP > 8-12 mm Hg MAP > 65 mm Hg Urine Output > 0.5 ml/kg/hr ScvO2 > 70% SaO2 > 93% Hct > 30%

*

Early Direct Goal Treatment in Sepsis Resucitation

Rivers E, Nguyen B, Havstad S, et al. N Eng J Med 2001;345:1368-77

B. Diagnosis

Obtain appropriate cultures before starting antibiotics Obtain >2 BCs >1 BCs should be percutaneous 1 BC from each vascular access device in place >48 hrs Culture other sites as clinically indicated

Imaging studies to confirm and sample any source of infection

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Why Do We Need Why Do We Need Culture(s)?Culture(s)?

Confirm infection

Confirm the responsible pathogens

Susceptibility profile de-escalation of antibiotic therapy

BC negative in 50%, BUT very likely caused by bacteria/ fungi decisions must be made by clinician judgment!

Weinstein MP, Reller LP, Murphy JR, et al.Rev Infect Dis; 5:35–53

C. Antibiotic TherapyGeneral Concept in Emprical AntibioticsTherapy

Spectrum of antibiotics Organ system involved Pharmacokinetics Safety profile Cost


Selection of Antibiotic

Local susceptibility pattern Clinical experience Site of infections Potential toxicities Cost


Kreger BE et al. Am J Med 1980;68:332-43.Meehan TP et al. JAMA 1997;278:2080-4.Opal SM et al. Crit Care Med 1997;25:1115-24.Pittet D et al. Am J Respir Crit Care Med 1996;153:684-93.Simon D et al. Crit Care Clin 2000;16:215-31.

Appropriate antibioticsreduce mortality by 10%-15%; mortality remains 28%-50%

Severe SepsisSevere Sepsis

DeathDeath

Courtesy of the National Initiative in Sepsis Education. Copyright © 2002 Thomson Advanced Therapeutics Communications™ (ATC) and Vanderbilt University School of Medicine. All rights reserved.

Antibiotics and Sepsis:Antibiotics and Sepsis:Necessary But Not Sufficient for SurvivalNecessary But Not Sufficient for Survival

Outcome: Stopping Progression of Disease

Appropriate antibioticsdecrease evolution tosevere sepsis by ~50%

InfectionInfection

Inflammation/Coagulation ActivationInflammation/Coagulation Activation

Strategy For Empirical TreatmentStrategy For Empirical Treatment PatientPatient

Outpatient HospitalizedOutpatient Hospitalized

Stable condition Severe or Stable condition Severe or high riskhigh risk

Escalation Escalation

DeescalationDeescalation

AntibioticAntibiotic selection based on selection based on Susceptibility and resistance patternSusceptibility and resistance pattern Immunity status, co morbidity and organ Immunity status, co morbidity and organ

dysfunctiondysfunction

Antibiotic Antibiotic monotherapy or combinationmonotherapy or combination

Pohan HT, 2005

Serious hospital-acquired infection suspected

Microbiological samples

Empirical antimicrobial treatment with a combination of agents targeting the most common

pathogens based on local data

Follow clinical parameters

De-escalate antimicrobials based on results of clinical microbiology data

Follow clinical parameters

Significant clinical improvement after 48 – 96 hours

Discontinue antimicrobials after 7 - 14 day course based on site of infection and clinical response

Search for super infection abscess formation,

noninfectious causes of fever, inadequate tissue

penetration YesYes

NoNo

A flow diagram illustrating the de-escalation approach to antimicrobial treatment for hospital-acquired infections

Kollef MH: Drugs 2003;63:20

Empirical Antimicrobial Therapy in SepsisEmpirical Antimicrobial Therapy in Sepsis

SourceSource Preferred TherapyPreferred Therapy Alternate therapyAlternate therapy

Unknown Unknown sourcesource

MeropenemMeropenem

Piperacillin/tazobactamPiperacillin/tazobactam

Fluoroquinolones +Fluoroquinolones +

Metronidazole / clindamycinMetronidazole / clindamycin

CAPCAP QuinoloneQuinolone

CeftriaxoneCeftriaxone

22ndnd gen cephalosporin gen cephalosporin

CefepimeCefepime

Nosocomial Nosocomial pneumoniapneumonia

MeropenemMeropenem

LevofloxacinLevofloxacin


Cunha BA, et al. In: Cunha BA, et al. Antibiotic essentials. 2008.

Empirical Antimicrobial Therapy in SepsisEmpirical Antimicrobial Therapy in Sepsis

SourceSource Preferred TherapyPreferred Therapy Alternate therapyAlternate therapy

Intraabdominal Intraabdominal / pelvic source/ pelvic source

MeropenemMeropenem


ErtapenemErtapenem

Ceftriaxone + MetronidazoleCeftriaxone + Metronidazole

Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin) +Levofloxacin) +

Metronidazole / ClindamycinMetronidazole / Clindamycin

Urosepsis – Urosepsis – Community-Community-

acquiredacquired

MeropenemMeropenem


Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin)Levofloxacin)

Aminoglycoside + Aminoglycoside + Ampicillin / VancomycinAmpicillin / Vancomycin

Urosepsis – Urosepsis – NosocomialNosocomial

MeropenemMeropenem


AztreonamAztreonam

CefepimeCefepime

AmikacinAmikacin

Cunha BA, et al. In: Cunha BA, et al. Antibiotic essentials. 2008.

D. Source ControlD. Source Control A specific anatomic site of infection should be

established within first 6 hrs

Implement source control measures as soon as possible following successful initial resuscitation (exception: infected pancreatic necrosis surgical intervention is best delayed)

Choose source control measure with maximum efficacy and minimal physiologic upset

Remove intravascular access devices if potentially infected

Mier J, Leon EL, Castillo A, et al. Am J Surg 1997; 173: 71–75Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Source Control Source Control Technique Choices Choices

Technique ExampleDrainage Intra-abdominal abscess

Thoracic empyema

Septic arthritis

Debridement Pyelonephritis, cholangitis

Infected pancreatic necrosis

Intestinal infarction

Mediastinitis

Device removal Infected vascular catheter

Urinary catheter

Infected intrauterine

contraceptive device

Definitive control Sigmoid resection for diverticulitis

Cholecystectomy for gangrenous cholecystitis

Amputation for clostridial myonecrosis

Jimenez MF, Marshall JC. Intensive Care Med 2001; 27:S49–S62

Suportive Therapy in Sepsis

OxygenizationFluid and volume resuscitationAlbumineBlood transfusionVasopresor and inotropicNutritionBlood glucose controlledRenal dysfunctionBicarbonate therapyCorticosteroidsCoagulation disorders

Jindal N, Hollenberg SM, Dellinger RP. Crit Care Clin 2000;16(2):233-49

Some Immunomodulatory Therapy in Sepsis

Antiendotoxin therapy Monoclonal or polyconal antibodies LPS analog, LPS elimination

Specific mediators anti TNF TNF receptors IL-1 RA Coagulants (AT, activated protein C) Tissue factor pathway inhibitors PAF Arachidonic metabolites Bradikinin antagonist Nitric oxide synthase inhibitors

Immunostimulation Immunoglobulins G-CSF IFN Immunonutrition

Non specificCorticosteroids Pentoxifillin Hemofiltration

Vincent JL, Sun Q, Duboid MJ. Clin Infec Dis 2002;34:1084-93

Conclusions

Early diagnosis and appropriate treatment of sepsis Role of clinician and intensivist in the management of sepsis in hospital and intensive care unit Important of appropriate antibiotics and removing source of infection in success of sepsis treatment Supportive care is important to maintain patients in stable condition

Conclusions

Potential used of antimediators and immuno- therapy for the future treatment of sepsis still need more data for specific usage. Interdiciplinary coordination and team work are needed for holistic approach for management of septic patients.

SEPSIS Kuliah Prof Herdiman (S1) Rev 17112011

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