Sepsis

Marshell Tendean, DPCP

Department of Internal Medicine
UKRIDA Faculty of Medicine Jakarta

Objective
To review the history of sepsis and septicemia
To explain the pathophysiology of sepsis
To review approach to sepsis
To review empiric antibiotic given for sepsis
To review the supporting treatment for sepsis

Introduction
For the Ancient Greeks, sepsis referred to rot, decay, or
putrefaction.
Galen and Celsus described the signs of inflammation
as peripheral vasodilatation (rubor), fever (calor), pain
(dolor), increased capillary permeability (tumor), and
organ dysfunction (functio laesa).

Lancet: 381 March 2, 201

1992
American College of Chest Physicians (ACCP) and the Society of Critical
Care Medicine (SCCM

SIRS
Infection
Sepsisis defined as "a microbial
phenomenon characterized by an inflammatory
Severe sepsis
response to the microorganisms or the invasion
Septic
of
normally shock
sterile tissue by those organisms.
MODS
Bacteremia is the presence of bacteria within
the bloodstream, but this condition does not
always lead to SIRS or sepsis.

Chest 1992:101: 1644-55

1992
American College of Chest Physicians (ACCP) and the Society of Critical
Care Medicine (SCCM

Sepsis
SIRS
is defined as 2 or more of the
Infection plus
following
variables
2 SIRS
criteria

Fever of more
than 38C (100.4F) or
SevereSepsis
Sepsis
less
Organ
Hypoperfusion
thandysfunction
36C (96.8F)
Larate
ctic of
acidosis
Heart
more than 90 beats per

Oliguria

minute
Altered mental status
Respiratory rate of more than 20
Septicshock
breaths
Severe per
Sepsis
minute or arterial carbon
dioxide
Hypotension
despite
Resuscitation BP
tension
(PaCOfluid
2) of less than
<90 or SBP decrease >40 mmHg
32
mm Hg
Inotropic or vasopressor agents
Abnormal white blood cellSyndrome
count
MultipleOrganDysfunction
(MODS)
or <
4,000/L
(>12,000/L
Altered organ
function
inor
an>10%
acutely ill
patient [band] forms)
immature

Homeostasis cannot be maintained

Chest 1992:101: 1644-55

2011
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

Crit Care Med 2003; 31: 12501256.

2011
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

Crit Care Med 2003; 31: 12501256.

2011
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

Crit Care Med 2003; 31: 12501256.

Causes

BMJ 2016;353:i1585

Pathogenesis

BMJ 2016;353:i1585

Lancet 2013; 381: 77475

Target organ damage in sepsis

BMJ 2016;353:i1585

Approach to the patient with sepsis?

Q sofa dan Sofa clinical approach
The Bundle of Sepsis
Initial EGDT treatment for septic shock

2013
The Third International Consensus Definitions for Sepsis and Septic Shock
(Sepsis-3)

Sepsis is defined as life-threatening organ dysfunction caused by a

dysregulated host response to infection.
Organ dysfunction can be identified as an acute change in total SOFA
score 2 points consequent to the infection Severe sepsis as Sepsis
The baseline SOFA score can be assumed to be zero in patients not known to
have preexisting organ dysfunction.
A SOFA score 2 reflects an overall mortality risk of approximately 10% in a
general hospital population with suspected infection.

In those patients who have infection and hypotension or a lactate level

greater than or equal to 4 mmol/L, providing 30 mL/kg crystalloid with
reassessment of volume responsiveness or tissue perfusion should be
implemented. The six-hour elements of care should be completed.

2013
The Third International Consensus Definitions for Sepsis and Septic Shock
(Sepsis-3)

Septic shock is defined as a subset of sepsis in which

underlying circulatory, cellular and metabolic abnormalities are
associated with a greater risk of mortality than sepsis alone
Clinical criteria
Hypotension requiring use of vasopressors to maintain MAP 65

mmHg and having a serum lactate >2 mmol/l persisting despite

adequate fluid resuscitation
JAMA. 2016 Feb 23; 315(8): 801
810.

Recognition of Sepsis

Critical

SOFA score

Approach to patient with sepsis.

The Surviving sepsis bundle (2013)

Early goal directed therapy for

septic shock

N Engl J Med, Vol. 345,

Therapeutic strategies in sepsis

Control the infection source
Drainage (WITHIN 12 HOURS)
Surgical
Radiologically guided

Culture directed antimicrobial therapy

Support of reticuloendothelial system
Enteral / parenteral nutritial support
Minimize supportive therapies

Diagnostics
Cultures as clinically appropriate before antimicrobial
therapy if no signi cant delay (> 45 mins) in the start of
antimicrobial(s).
At least 2 sets of blood cultures (both aerobic and anaerobic
bottles) be obtained before antimicrobial therapy
Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and
anti-mannan antibody assays (grade 2C), if available and
invasive candidiasis is in differential diagnosis of cause of
infection.
Imaging studies performed promptly to con rm a potential
source of infection (UG).

Guideline recommendations
Administration of effective IV
antimicrobials within the 1st hour of
recognition of septic shock (grade 1B)
and severe sepsis without septic shock
(grade 1C)
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 (grade 1B)

Crit Care Med 2013;41:580-637

Early, appropriate antibiotics

Early = within 1 hour after
recognition of potential septic
shock
Appropriate = in vitro activity
against pathogen
Route of administration
Dose and frequency
Penetration
Cidality
Crit Care Clin 2011;27:53-76

Fraction of total patients

Effect of timing on survival

Time from hypotension onset (hours)

Adapted with permission from:
Crit Care Med 2006;34:1589-96

Effect of inappropriate antibiotics

on survival
Appropria Inappropr
te
iate
(n=4579) (n=1136)
Survived
Immunosuppressed*
COPD
Dialysis

OR (95% CI)

52

10.3

15

19.8

9.45
(7.74
P value
11.54)
< 0.05

13.6
7.3

14.1
10.7

< 0.05
< 0.05

All numbers expressed as % unless otherwise specified

* Immunosuppression = chemotherapy or chronic steroids (>10mg prednisone daily)

Chest 2009;136:1237-48

Risk Factors
MDR/Health-care
associated pathogens

broad spectrum antibiotics

within 90 d
hospitalization >5 d
local high antibiotic resistance
rates
residence in LTCF
chronic dialysis within 30 d
home wound care
family member with MDR
infection
mechanical ventilation 5 d
immunosuppression
structural lung disease
IV drug use
Clin Infect Dis 2007;44:S27-72
COPD (Pseudomonas spp.)
Am J Respir Crit Care Med
2005;171:388-416
Influenza infection (MRSA)

Fungemia

broad-spectrum antibiotics
central venous catheter
parenteral nutrition
renal replacement therapy in
ICU
neutropenia
hematologic malignancy
implantable prosthetic
devices
immunosuppression
chemotherapy

Clin Infect Dis 2009;49:1-45

Clin Infect Dis 2009;48:503-35

Guideline recommendations

Combination empirical therapy for the

following patients (grade 2B):
Neutropenic with severe sepsis and for
patients with difficult-to-treat, multidrugresistant bacterial 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

Combination therapy vs. monotherapy for

septic shock
Mortality rate *

28-Day, %

Monotherapy
(n=1223)

Combination
Rx (n=1223)

HR (95% CI)

36.3

29

0.77 (0.67
0.88)
0.75 (0.63
0.88)

ICU, %

35.7

28.8
# deaths

Hospital,
%,
All
Gram +
%

47.8
39.9

37.4
30.7

All Gram - ,
%

34.5

0.79 (0.67
28.2* Propensity score adjusted
0.94)

0.69 (0.59
0.73 (0.58
0.81)
0.92)

Crit Care Med 2010;38:1773-85

Antibiotic review: Sepsis from pulmonary

source
Infecti
on
CAP

Example antibiotic regimens

-lactam1 + azithromycin
-lactam1 + respiratory FQ2
HCAP
antipseudomonal -lactam3
+ aminoglycoside4 or antipseudomonal
5
1
FQcefotaxime,
ceftriaxone,
ampicillin/sulbactam
2
levofloxacin,
moxifloxacin or linezolid
+ vancomycin

piperacillin/tazobactam, cefepime, meropenem, imipenem,

doripenem
4
gentamicin, tobramycin, amikacin
5
levofloxacin, ciprofloxacin
3

Clin Infect Dis 2007;44:S27-72

Am J Respir Crit Care Med 2005;171:388-416

Antibiotic review: Sepsis from

catheter-related bloodstream
infection (CRBSI)
Infection
CRBSI

Example antibiotic regimens

vancomycin or daptomycin1
+ antipseudomonal -lactam2,3
+/- aminoglycoside4

Fungemia + fluconazole or echinocandin5

risk factors
1
2
3
4
5

if high rates of vancomycin MIC 2 g/mL

piperacillin/tazobactam, cefepime
meropenem, imipenem, doripenem
gentamicin, tobramycin, amikacin
caspofungin, micafungin, anidulafungin

Clin Infect Dis 2009;49:1-45

Antibiotic review: Sepsis from

urinary source
Infection

Example antibiotic
regimens
Urosepsis
3rd generation
cephalosporin1
+/- aminoglycoside2 or FQ3
Urological
antipseudomonal 1
ceftriaxone, cefotaxime
2
interventions
or MDR amikacin
lactam4,5
gentamicin, tobramycin,
3
risk
factors ciprofloxacin
levofloxacin,
piperacillin/tazobactam, cefepime
5
meropenem, imipenem, doripenem
4

Int J Urol 2013; Epub ahead of print.

ntibiotic review:
epsis from unknown source
Infection
Unknown

Example antibiotic regimens

antipseudomonal -lactam1,2
+ aminoglycoside or antipseudomonal
FQ3
+ vancomycin
+ fluconazole or echinocandin4

Fungemia
risk
1
piperacillin/tazobactam, cefepime
2
factors
meropenem, imipenem, doripenem

levofloxacin, ciprofloxacin
4
caspofungin, micafungin, anidulafungin
3

Clin Infect Dis 2009;48:503-35

Empiric antibiotic therapy

Corticosteroid
Not using intravenous hydrocortisone to treat adult
septic shock patients if adequate uid resuscitation and
vasopressor therapy are able to restore hemodynamic
stability (see goals for Initial Resuscitation). In case this
is not achievable, we suggest intravenous
hydrocortisone alone at a dose of 200 mg per day
In treated patients hydrocortisone tapered when
vasopressors are no longer required.
Corticosteroids not be administered for the treatment of
sepsis in the absence of shock.

 Support of dysfunctional organ system

Renal replacement therapies (CVVHD, HD)
Cardiovascular support (pressors, inotropes)
Mechanical ventilation
Glucose control
Transfussion for hematologic dysfunction
Stress ulcer prophylaxis
Minimize exposure to hepatotoxic and nephrotoxic therapies

Future Directions
Endotoxin-neutralizing proteins, inhibitors of
cyclooxygenase or nitric oxide synthase, anticoagulants,
polyclonal immunoglobulins, glucocorticoids, a
phospholipid emulsion, and antagonists to TNF-, IL-1,
platelet-activating factor, and bradykinin.
Unpromissing.

Prognosis
Patients with septic shock can be identified with a
clinical construct of sepsis with persisting hypotension
requiring vasopressors to maintain MAP 65 mm Hg and
having a serum lactate level >2 mmol/L (18 mg/dL)
despite adequate volume resuscitation.
With these criteria, hospital mortality is in excess of
40%.