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
Cunha B. In : Conn Current Therapy 2003
(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
Cunha B. In : Conn Current Therapy 2003
Selection of Antibiotic
Local susceptibility pattern Clinical experience Site of infections Potential toxicities Cost
Cunha B. In : Conn Current Therapy 2003
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
Piperacillin/tazobactamPiperacillin/tazobactam
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
Piperacillin/tazobactamPiperacillin/tazobactam
ErtapenemErtapenem
Ceftriaxone + MetronidazoleCeftriaxone + Metronidazole
Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin) +Levofloxacin) +
Metronidazole / ClindamycinMetronidazole / Clindamycin
Urosepsis – Urosepsis – Community-Community-
acquiredacquired
MeropenemMeropenem
Piperacillin/tazobactamPiperacillin/tazobactam
Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin)Levofloxacin)
Aminoglycoside + Aminoglycoside + Ampicillin / VancomycinAmpicillin / Vancomycin
Urosepsis – Urosepsis – NosocomialNosocomial
MeropenemMeropenem
Piperacillin/tazobactamPiperacillin/tazobactam
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.