SEPSIS

Edwin Jim
Tropical Medicine and Infectious Disease Division
Internal Medicine Department
Medical Faculty University of Indonesia
 Objectives
Define SIRS / sepsis / severe sepsis / septic shock
Early recognition of Sepsis
Early Therapy
Rangel-Frausto M et. al., JAMA 1995; 273:117-23
 A survival spectrum

SIRS, systemic inflammatory response syndrome. Rangel-Frausto MSet al. The natural history of the systemic
inflammatory response syndrome (SIRS). A prospective study. The journal of the American Medical
Association1995;273(2): 117–123.
Severe Sepsis is increasing in
incidence
Severe Sepsis cases US Population

1800 600
1600 550
500
1400
450
1200
400
1000
350
800 300
600 250
2001 2025 2050
 Inflammation

Tumor, dolor, rubor and calor.

 Causes of severe sepsis and
their relative frequencies
Pneumonia 50–60%
Intra-abdominal 20–25%
Urinary tract infection 7–10%
Soft tissue, bone, joint 5–10%
Endocarditis <5%
Meningitis <5%
Relationship Between Sepsis and SIRS
 Sepsis
Host’s 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
 Sepsis : a Disease Continuum

Septic Shock
Severe Sepsis
Sepsis

SIRS

Infection

Bone et al. Chest 1992;101:1644

 Infection

Inflammatory Endothelial
Vasodilation
Mediators Dysfunction

Hypotension Microvascular Plugging Vasoconstriction Edema

Maldistribution of Microvascular Blood Flow

Ischemia

Cell Death

Organ Dysfunction
Schematic representing stages in the natural course of sepsis and their interactions. Note that multiple
organ dysfunctions can also occur in the absence of overt shock through similar mechanisms.
Pro-inflammatory Mediators
• Bacterial Endotoxin
• TNF-α
• Interleukin-1
• Interleukin-6
• Interleukin-8
• Platelet Activating Factor (PAF)
• Interferon-Gamma
• Prostaglandins
• Leukotrienes
• Nitric Oxide
Anti-inflammatory Mediators
• Interleukin-10
• PGE2
• Protein C
• Interleukin-6
• Interleukin-4
• Interleukin-12
• Lipoxins
• GM-CSF
• TGF
• IL-1RA
 Updated Definition
SIRS (Systemic inflammatory response syndrome):
- Clinical syndrome that results from a deregulated inflammatory
response or to a noninfectious insult.
Sepsis
– Infection (documented/suspected) + systemic manifestations
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
in the absence of other cause of hypotension
Septic Shock
– Sepsis-induced hypotension persisting despite adequate fluid resuscitation
Bone, et al. 1992 Chest 101:1644-1655
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327
 Definitions
A continuum of severity describing the host systemic inflammatory response
 Adult Sepsis/Severe Sepsis Criteria
• SIRS (Systemic inflammatory response syndrome):
- Hyperthermia >38.3°C or Hypothermia <36°C
- Acutely Altered Mental Status
- Tachycardia >90 bpm
- Tachypnea >20 bpm
- Leukocytosis (>12,000 µL-1) or Leukopenia (<4,000 µL-1) or >10% bands
- Hyperglycemia (>120 mg/dl) in the absence of diabetes
• Signs of hypoperfusion or organ dysfunction:
- Hypotension (<90/60 or MAP <65) - Lactate >2
- Areas of mottled skin or capillary refill >3 seconds
- Creatinine >2.0 mg/dl - DIC
- Platelet count <100,000 - Acute lung injury or ARDS
- Acute renal failure or urine output <0.5 ml/kg/hr for at least 2 hours
- Hepatic dysfunction as evidenced by Bilirubin >2 or INR >1.5
- Cardiac dysfunction
 Systemic Manifestations
I. General variables
Fever (38.3°C)
Hypothermia (core temperature 36°C)
Heart rate > 90/min or 2 SD above normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (20 mL/kg over 24 hrs)
Hyperglycemia (plasma glucose 140 mg/dL or 7.7 mmol/L) in the absence of
diabetes

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327
 Systemic Manifestations
II. Inflammatory variables
Leukocytosis (WBC count >12,000/μL)
Leukopenia (WBC count <4000/μL)
Normal count with >10% immature WBC
Plasma CRP >2 SD above normal value
Plasma PCT >2 SD above normal value

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327
 Septic Shock
Septic Shock - Severe sepsis plus one of the following
conditions:
– MAP <60 mm Hg (<80 mm Hg if previous hypertension) after
adequate fluid resuscitation
– Need for pressors to maintain BP after fluid resuscitation
– Adequate fluid resuscitation = 40 to 60 mL/kg saline solution
(NS 5L-10L)
– Lactate > 4mmol /L
 Orthogonal polarization spectral image of the
microcirculation during sepsis (b) and in health (a)

Courtesy: Prof. C Ince and Dr P Goedhart, Amsterdam, Holland.

 Severe Sepsis Recommendations

1. Early Detection
2. Early Treatment
• Sepsis Resuscitation Bundle
3. Monitor reliability and outcomes
 Surviving Sepsis Campaign:
International Guidelines for
Management of Severe Sepsis and Septic Shock, 2012

A. Initial resuscitation
B. Screening for sepsis and performance improvement
C. Diagnosis
D. Antimicrobial therapy
E. Source control
F. Infection prevention
G. Fluid therapy
H. Vasopressors
I. Inotropic therapy
J. Steroids
Other supportive therapy

Crit Care Med 2013;41:580-637

 Initial resuscitation
A = Airway assessment, maintenance and oxygen
B = Breathing and ventilation assessment
C = Circulation assessment, intravenous (IV) access & fluids
D = Disability: assess neurological status & check B.Glucose
E = Exposure and environmental control
Resuscitation Bundle
3-hour and 6-hour Bundle Division

• 3-hour Bundle – Actions to be taken within the first 3 hours of resuscitation

from initial recognition for adults.

• 6 – hour Bundle – Actions to be taken within the first 6 hours of resuscitation

from initial recognition for adults.
 Two treatment track – invasive or non-invasive
 Track followed is based on the criticality and initial response to hemodynamic
measures.
Resuscitation Bundle
3-hour Bundle

• Serum lactate measured within 3 hours of presentation in adults

• Blood cultures obtained prior to antibiotic administration; additional cultures to
determine potential site of infection
( 2 Sets, one peripheral and one from any line older than 48hrs)
• Early and appropriate broad-spectrum antibiotic administration
• within 3 hour for ED presentation.
• within 1 hour for floors/ICU presentation.
• Combination therapy for neutropenic and pts with pseudomonas risk factors

• In the event of hypotension and/or a lactate >4 mmol/L, deliver

a minimum of 30 ml/kg of fluids in adults.
 Fluid therapy
Central Line Access (Fluid hydration +/- pressor)
1st line therapy – fluids, fluids, fluids!
Crystalloid equivalent to colloid
Initial 1-2 Liters (20mg /kg) crystalloid or 500 ml colloid
Use of albumin in severe sepsis & septic shock when pts
require substantial amounts of crystalloids (Grade 2C).
Careful in CHF patients !!
 Resuscitation of Sepsis
Induced Tissue Hypoperfusion

Recommend MAP 65 mm Hg
FLUID THERAPY
Resuscitation Bundle
6-hour Bundle
• Vasopressor therapy for persistent hypotension (MAP <65 in adults)
despite initial fluid administration.
• Norepinephrine as the first choice vasopressor (Grade 1 B).
• Re-measure lactate if the initial value was elevated

• Invasive
 A central venous catheter capable of measuring CVP
• Non-invasive
 Contraindications for invasive track
 Trending of lactate levels to gauge fluid response
 Antibiotics and Sepsis:
Necessary But Not Sufficient for Survival

Infection Appropriate antibiotics

decrease evolution to
severe sepsis by ~50%
Inflammation/Coagulation Activation

Appropriate antibiotics
Severe Sepsis reduce mortality by
10%-15%; mortality
remains 28%-50%
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.
Courtesy of the National Initiative in Sepsis Education. Copyright © 2002 Thomson Advanced Therapeutics
Communications™ (ATC) and Vanderbilt University School of Medicine. All rights reserved.
Why Do We Need 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
 Appropriate Culture(s)
SSC 2012: Guideline recommendations
Cultures as clinically appropriate before antimicrobial therapy
if no significant delay (> 45 mins) in the start of antimicrobial(s)
(1C)
At least 2 sets of blood cultures (both aerobic and anaerobic bottles
(1C):
– at least 1 drawn percutaneously
– and 1 drawn through each vascular access device, unless the
device was recently (<48 hrs) inserted

Crit Care Med 2013;41:580-637

 What Is Considered
“Appropriate” Antimicrobial Treatment?
SSC 2012: Guideline recommendations

WHEN?
 Administration of effective IV antimicrobials within the 1st hour of
recognition of septic shock (1B) and severe sepsis without septic
shock (1C)
 Need for “sense of emergency” as the concept of “door to needle”
time in acute coronary syndrome cases

Crit Care Med 2013;41:580-637

 Effect of timing on survival

Fraction of total patients

Time from hypotension onset (hours)

Crit Care Med 2006;34:1589-96
 Examples of sources of sepsis, cultures to take and
potential pathogens
Source Sample Potential pathogen
Urinary tract Urine Escherichia coli, Proteus, Klebsiella
Meningitis Cerebrospinal Streptococcus pneumoniae, Neisseria
fluid meningitidis, Haemophilus influenzae, E. coli
Cellulitis Skin swab Group A Streptococcus, Staphylococcus
Epiglottitis Epiglottic swab H. influenzae type B,S. pneumoniae
Lungs Sputum S. pneumoniae, Staphylococcus aureus,
H. influenzae, Klebsiella pneumoniae, E. coli

Tim Nutbeam, 2010

 Organisms commonly isolated from blood cultures
and their most likely sources
Organism from blood Examples of sources
culture
Escherichia coli Urinary tract, intra-abdominal
Streptococcus pneumoniae Pneumonia, meningitis
Staphylococcus aureus Skin, soft tissue, wound, osteomyelitis, septic arthritis,
pneumonia, endocarditis, intravascular devices
Streptococcus pyogenes Cellulitis, necrotizing fasciitis
Streptococcus milleri group Pus/abscess in lung, liver, abdomen
Coagulase-negative Prosthetic joint/heart valve, central line, ventriculo-
staphylococci peritoneal shunt
Candida albicans Neutropaenia, abdominal surgery, central line
infections
Tim Nutbeam, 2010
 What Is Considered
“Appropriate” Antimicrobial Treatment?
SSC 2012: Guideline recommendations

WHAT ?
 Initial empiric anti-infective therapy of one or more drugs that have activity
against all likely pathogens and that penetrate in adequate concentrations
into tissues presumed to be the source of sepsis (1B)
 Combination empirical therapy for certain patients (2B)

Crit Care Med 2013;41:580-637

The Importance of Initial Empiric Antibiotic
Selection
Adequate initial antibiotic treatment
100
Inadequate initial antibiotic treatment
80
Mortality (%)

60

40

20

0
Alvarez- Dupont Kollef (1999) Luna (1997) Rello (1997) Ruiz (2000)
Lerma (1996) (2001) P < 0.001 P < 0.001 P < 0.05 P = NS
P = NS P < 0.05

1. Alvarez-Lerma F. Intensive Care Med. 1996;22:387-394. 4. Luna CM, et al. Chest. 1997;111:676-685.
2. Dupont H, et al. Intensive Care Med. 2001;27:355-362. 5. Rello J, et al. Am J Respir Crit Care Med. 1997;156:196-200.
3. Kollef MH, et al. Chest. 1999;115:462-474. 6. Ruiz M, et al. Am J Respir Crit Care Med. 2000;162:119-125.
 Combination Empirical Therapy
SSC 2012: Guideline recommendations
 Combination empirical therapy for the following patients (2B):
• Neutropenic with severe sepsis
• Patients with difficult-to-treat, MDR pathogens (Acinetobacter or Pseudomonas
bacteremia)
• Severe infections associated with respiratory failure and septic shock
(Pseudomonas bacteremia)
• Septic shock from bacteremic Streptococcus pneumoniae

Crit Care Med 2013;41:580-637

 Empiric Antibiotic Choices:
Sepsis from Pulmonary Source
Infection Example antibiotic regimens
CAP β-lactam1 + azithromycin
β-lactam1 + respiratory FQ2
HCAP antipseudomonal β-lactam3
+ aminoglycoside4 or antipseudomonal FQ5
+ vancomycin or linezolid
1 ceftriaxone, cefotaxime, ampicillin/sulbactam
2 levofloxacin, moxifloxacin
3 piperacillin/tazobactam, cefepime, meropenem, imipenem, doripenem
4 gentamicin, tobramycin, amikacin
5 levofloxacin, ciprofloxacin

Clin Infect Dis 2007;44:S27-72

Am J Respir Crit Care Med 2005;171:388-416
 Empiric Antibiotic Choices:
Sepsis from cIAI
Infection Example antibiotic regimens
Community Imipenem-cilastatin, meropenem, doripenem,
acquired and piperacillin-tazobactam OR
Cefepime, ceftazidime, ciprofloxacin, or levofloxacin,
each in combination with metronidazol
Health care- Carbapenem, piperacillin-tazobactam
associated Vancomycin in high insidence of local institution

Solomkin JS. Clinical Infectious Diseases 2010; 50:133–64

 Empiric Antibiotic Choices:
Sepsis from SSTI
Infection Example antibiotic regimens
Purulent Vancomycin or linezolid

Non purulent Piperacillin-tazobactam plus vancomycin

Clindamycin or metronidazol PLUS aminoglycoside or
FQ
Carbapenem
Cefotaxime PLUS metronidazole atau clindamycin

Stevens DL. Clin Infect Dis 2014

 Empiric Antibiotic Choices:
Sepsis from CRBSI
Infection Example antibiotic regimens
CRBSI vancomycin or daptomycin1
+ antipseudomonal β-lactam2,3
+/- aminoglycoside4
Fungemia + fluconazole or echinocandin5
risk factors
1 if high rates of vancomycin MIC ≥ 2 µg/mL
2 piperacillin/tazobactam, cefepime
3 meropenem, imipenem, doripenem
4 gentamicin, tobramycin, amikacin
5 caspofungin, micafungin, anidulafungin

Clin Infect Dis 2009;49:1-45

 Empiric Antibiotic Choices:
Sepsis from Urinary Source
Infection Example antibiotic regimens
Urosepsis 3rd generation cephalosporin1
+/- aminoglycoside2 or FQ3
Urological interventions or antipseudomonal β-lactam4,5
MDR risk factors
1 ceftriaxone, cefotaxime
2 gentamicin, tobramycin, amikacin
3 levofloxacin, ciprofloxacin
4 piperacillin/tazobactam, cefepime
5 meropenem, imipenem, doripenem

Int J Urol 2013; Epub ahead of print.

 Empiric Antibiotic Choices:
Sepsis from Unknown Source
Infection Example antibiotic regimens
Unknown antipseudomonal β-lactam1,2
+ aminoglycoside or antipseudomonal FQ3
+ vancomycin
Fungemia + fluconazole or echinocandin4
risk factors
1 piperacillin/tazobactam, cefepime
2 meropenem, imipenem, doripenem
3 levofloxacin, ciprofloxacin
4 caspofungin, micafungin, anidulafungin

Clin Infect Dis 2009;48:503-35

 Strategy for Optimalization of
Antibiotic Therapy
Antibiotic Dosing
Concentration dependent Once daily large bolus
(Cmax/MIC)
Time dependent (T> MIC) Loading followed by prolonged/
extended infusion of total daily
dose
AUC/MIC Multiple bolus doses
Therapeutic Strategies in Sepsis
• Control Infection Source

• Drainage
• Surgical
• Radiologically-guided

• Culture-directed antimicrobial therapy

• Support of reticuloendothelial system

• Enteral / parenteral nutritional support
• Minimize immunosuppressive therapies
Therapeutic Strategies in Sepsis
• Support Dysfunctional Organ Systems

• Renal replacement therapies (CVVHD, HD).

• Cardiovascular support (pressors, inotropes).

• Mechanical ventilation.

• Transfusion for hematologic dysfunction.

• Minimize exposure to hepatotoxic and nephrotoxic

therapies.
THANK YOU