Holistic Approach in Management of Sepsis

Herdiman T. Pohan
Tropical Medicine and Infectious Disease Division Internal Medicine Department Medical Faculty University of Indonesia

Sepsis
Hosts reaction to systemic invading microbes involves a rapidly amplifying inflammatory signals and responses that may spread beyond the invaded tissue. When counterregulatory control mechanisms are overwhelmed, homeostasis may fail, and dysfunction of major organ may supervene. Further imbalance response related to hypotension and septic shock with multiple organ dysfunction leads to increasing deaths

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

P I R O

Predisposition Infection Response Organ Failure

Systemic Inflammatory Response Syndrome (SIRS)

Host response to Inflammation include 2 of:

1. Temp >38oC or <36oC 2. Heart rate >90x/ 3. Respiratory rate >20x/ or PaCO2<32mmHg 4. White blood cells count >12.000/mm3, < 4.000 or bands >10%

Bone et al. Chest 1992;101:1644

Sepsis : a Disease Continuum

Septic Shock
Severe Sepsis Sepsis SIRS

Infection
Bone et al. Chest 1992;101:1644

Infection
Microorganism invading sterile tissue

SIRS

Sepsis

Severe Sepsis Septic Shock

Sepsis with organ failure Vascular collapse Renal Hemostasis Lung LA

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

SIRS with a presumed or confirmed infectious process

Refractory hypotension

Chest 1992;101:1644

Updated Definition

Sepsis

SIRS (systemic manifestations) + Infection (documented/ suspected) Sepsis + sepsis-induced organ dysfunction or tissue hypoperfusion 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 Sepsis-induced hypotension persisting despite adequate fluid resuscitation
Bone, et al. 1992 Chest 101:1644-1655 Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Severe sepsis

Sepsis-induced hypotension

Septic Shock

Criteria of Organ Dysfunction

Aterial hypotension (MAP<70) SCVO2 >70% CI>3.5 L/mt/m2 Arterial hypoxemia (PaO2/FiO2 <300) Acute oliguria (urine output<0.5ml/kg/h for at least 2 hours) Creatinin increase >0.5mg/dL Coagulation abnormalites (INR >1.5 or aPTT > 60 sec) Ileus Thombocytopenia <100.000/uL Hyperbilirubinemia >4 mg?dL Hyperlactatemia >3 mmol/L Tissue Perfusion Decrease capilary fill
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definition Cofence,2001 Emergency Medicine 2010

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

Binding of Lipopolysacharida of Gram-negative bacilli

CD 14 TLR-2 TLR-4

Binding of Peptidoglycan of Gram-positive bacilli

Transcription of immunomodulatory cytokines (TNF-, interlukin-1, interleukin-10) NF-k

Release of NF-k and transfer 10 nucleus

Sepsis
Increased activity of iNOS Increased NO

Prostaglandins Leukotrienes Proteases Oxidants

Activation and binding of macrophage

NO
Vasodilation

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

Clinical conditions associated with sepsis

Gastrointestinal Liver Gallbladder Colon Intraabdominal abscess Intestinal obstruction Intraabdominal instrumentation Genitourinary Acute pyelonephritis Renal abscess Renal calculi Urinary tract obstruction Prostatic abscess Instrumentation Pelvic Pelvic abscess, peritonitis Intravascular Central iv line Infected prostetic device Septic thrombophlebitis Lower respiratory tract Community acquired pneumonia Nosocomial pneumonia Empyema Lung abscess Cardiovascular Acute bacterial endocarditis Myocardial abscess Central 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 bleeding Genitourinary Urethritis Cystitis Cervicitis Vaginitis Catheter associated bacteriuria in immunocompetent Upper respiratory tract Pharingitis Sinusitis Bronchitis Lower respiratory tract Community acquired pneumonia in immunocompetent Acute respiratory distress syndr Pulmonary hemorrhage Pulmonary vasculitis Cardiovascular Subacute bacterial endocarditis Myocarditis Pericarditis Cardiac tamponade Skin and soft tissue Septic arthritis Acute/chronic osteomyelitis Uncomplicated wound infection Decubitus ulcers
Cunha B. In : Conn Current Therapy 2003

Why Mortality Remains High??

(A) INFECTIOUS AGENT (S) : toxin & other virulence factors (B) HOST DEFENSES : natural barriers, humoral & cell-mediated immunity

(C) UNFAVORABLE HOST FACTORS Increasing age Breakdown of barriers Acquired immunodeficiency syndrome Diabetes melitus Cancer Asplenia End-organ disease Neutropenia, lymphopenia Chemotherapy, steroids & other Immunosuppressive agents

(D) MANAGEMENT Resuscitative and supportive measures Appropriate and timely antibiotics Targeted diagnostics Closer monitoring (triaging) Source control or anatomic repair : surgery, interventional radiology, etc. Reduction of immunosuppression Adjunctive medical therapy (e.g. IVIG, activated protein C, etc.)

Death

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

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

Management of Sepsis in Hospital Setting and Intensive Care Units

Clinicians Infectious Diseases Intensive Care Surgeons

Nephrologist Hematologist

Surviving Sepsis Campaign:

International Guidelines for Management of Severe Sepsis and Septic Shock, 2008
A.
B. C. D.

E.
F. G. H.

I.
J.

Initial resuscitation Diagnosis Antibiotic therapy Source control Fluid therapy Vasopressors Inotropic therapy Steroids Recombinant human activated protein C Blood product administration

Supportive Therapy

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

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 cant 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

EARLY GOAL DIRECT THERAPY (EGDT)

Infection SIRS Sepsis Severe Sepsis Septic Shock
CVP > 8-12 mm Hg MAP > 65 mm Hg Urine Output > 0.5 ml/kg/hr ScvO2 > 70% SaO2 > 93% Hct > 30%

Early Goal Directed Therapy

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.

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 Culture(s)?

Confirm infection
Confirm the responsible pathogens

Susceptibility profile deescalation 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; 5:3553

C. Antibiotic Therapy General Concept in Emprical Antibiotics Therapy

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

Necessary But Not Sufficient for Survival

Infection Appropriate antibiotics decrease evolution to severe sepsis by ~50%

Antibiotics and Sepsis:

Outcome: Stopping Progression of Disease

Inflammation/Coagulation Activation

Severe Sepsis

Death
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 antibiotics reduce mortality by 10%-15%; mortality remains 28%-50%

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

Strategy For Empirical Treatment

Patient Outpatient Hospitalized

Stable condition Escalation

Severe or high risk Deescalation

Antibiotic selection based on Susceptibility and resistance pattern Immunity status, co morbidity and organ dysfunction

Antibiotic monotherapy 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

Search for super infection abscess formation, noninfectious causes of fever, inadequate tissue penetration Follow clinical parameters

No

Significant clinical improvement after 48 96 hours

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

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 Sepsis

Source Preferred Therapy
Meropenem Piperacillin/tazobactam Quinolone Ceftriaxone Meropenem Levofloxacin Piperacillin/tazobactam

Alternate therapy
Fluoroquinolones + Metronidazole / clindamycin 2nd gen cephalosporin Cefepime

Unknown source
CAP Nosocomial pneumonia

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

Empirical Antimicrobial Therapy in Sepsis

Source Preferred Therapy Alternate therapy

Intraabdominal / pelvic source

Meropenem Fluoroquinolones (Ciprofloxacin / Piperacillin/tazobactam Levofloxacin) + Ertapenem Ceftriaxone + Metronidazole Metronidazole / Clindamycin
Meropenem Piperacillin/tazobactam Fluoroquinolones (Ciprofloxacin / Levofloxacin) Aminoglycoside + Ampicillin / Vancomycin Aztreonam Cefepime Amikacin

Urosepsis Communityacquired

Urosepsis Nosocomial

Meropenem Piperacillin/tazobactam

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

D. 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: 7175 Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Source Control Technique Choices

Technique
Drainage
Intra-abdominal abscess Thoracic empyema Septic arthritis Pyelonephritis, cholangitis Infected pancreatic necrosis Intestinal infarction Mediastinitis Infected vascular catheter Urinary catheter Infected intrauterine contraceptive device Sigmoid resection for diverticulitis Cholecystectomy for gangrenous cholecystitis Amputation for clostridial myonecrosis
Jimenez MF, Marshall JC. Intensive Care Med 2001; 27:S49S62

Example

Debridement

Device removal

Definitive control

Suportive Therapy in Sepsis

Oxygenization Fluid and volume resuscitation Albumine Blood transfusion Vasopresor and inotropic Nutrition Blood glucose controlled Renal dysfunction Bicarbonate therapy Corticosteroids Coagulation 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 g Immunonutrition

Non specific Corticosteroids 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 immunotherapy 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.