Objectives

• Understand the current nomenclature

• Know the local organisms
• Understand the spectrum of presenting illness
• Get a handle on the basic treatment
• Introduce novel treatments
 The Increasing Importance of the
Intensive Care Unit 50
374

372 48
Mean no of hospital beds

370
46

Mean no of ICU beds

368
44
366
42
364
Though ICUs account for only 8% of hospital beds,
362 40

45% of infections in a hospital originate in an ICU

360 38

358
36
1988 1989 1990 1991 1992 1993 1994 1995
356

Seminars in Respiratory and critical care med 2003,24(1):3-

Clin Infect Dis 1997;24:211-215 22,
Distribution of major sites of
infection in medical ICU’s
CVS GI LRI PN UTI BSI SST EENT
3% 3% 5%
5%
6%
16%

30%

30%

Ref. : Seminars in Respiratory and critical care med 24(1):3-22,2003

 Nosocomial troika
extended
……..
• S.aureus
• E.coli
• Pseudomonas aeruginosa

•K.Pneumoniae
•Enterobacteriaceae

•Citrobacter fruendii
Eight most common pathogens associated with
nosocomial infection in an ICU, NNIS January
1989 - July 1998
Clinics in Chest Medicine 1999; Vol 20: No: 2,JAC 2003; 51, Suppl S2, 115-117

All sites BSI PNEU UTI SSI Others

n=235,758 n=50,091 n=64,056 n=47,502 n=22,043 n=52,066

Coagulase 14.3 39.3 2.5 3.1 13.5 15.4

negative
staphylococci
S. aureus 11.4 10.7 16.8 1.6 12.6 13.7
P. aeruginosa 9.9 3.0 16.1 10.6 9.2 8.7
Enterococci spp. 8.1 10.3 1.9 13.8 14.5 5.9

Citrobacter spp. 7.3 4.2 10.7 5.7 8.8 6.8

E. coli 7.0 2.9 4.4 18.2 8.1 4.0

Candida 6.6 4.9 4.0 15.3 4.8 4.3
Albicans
Klebsiella 4.7 2.9 6.5 6.1 3.5 3.5
• For Sepsis High Risk Patients
– Post op / post procedure / post trauma
– Post splenectomy (encapsulated organisms)
– Cancer
– Transplant / immune supressed
– Alcoholic / Malnourished
• For Dying
– Genetic predisposition (e.g. meningococcus)
– Delayed appropriate antibiotics
– Yeasts and Enterococcus
– Site
• For Both
– Cultural or religious impediment to treatment
 Sepsis: Defining a Disease
Continuum

Infection/
Trauma SIRS Sepsis Severe Sepsis

A clinical response arising SIRS with a presumed

from a nonspecific insult, or confirmed
including  2 of the following: infectious process
• Temperature 38oC or 36oC
• HR 90 beats/min
• Respirations 20/min SIRS = Systemic Inflammatory Response Syndrome
• WBC count 12,000/mm3 or
4,000/mm3 or >10% immature
neutrophils

Chest 1992;101:1644,Crit Care Med 2000;28:S81

 Sepsis: Defining a Disease
Continuum

Infection/
Trauma SIRS Sepsis Severe Sepsis

Sepsis with 1 sign of organ

failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory
Hepatic Shock
Hematologic
CNS
Metabolic acidosis

Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207
 Definitions
• Sepsis = SIRS + Infection
• SIRS = 2/4 of
• Temp >38 or <36
• HR >90
• Respiratory Rate >20 or PaCO2 <32 (4.3kPa)
• WCC >12 or <4 or >10% bands
• Infection = either
• Bacteraemia (or viraemia/fungaemia/protozoan)
• Septic focus (abscess / cavity / tissue mass)
 Definitions Cont.
• Severe sepsis = Sepsis + Organ Dysfunction
• Organ Dysfunction = Any of
• SBP <90 or 40 <usual or inotrope to get MAP 90
• BE <-5mmol/L
• Lactate >2mmol/L
• Oliguria <30ml/hr for 1 hour
• Creatinine >0.16mmol/L
• Toxic confusional state
• FIO2 >0.4 and PEEP >5 for oxygenation
 Definitions Cont.
• Septic Shock = Severe sepsis + Hypotension

• Hypotension = either
• SBP <90 or 40<usual
• Inotrope to get MAP >90
 Sepsis the systemic response to infection
Pathophysiology : a continuum
A disorder due to uncontrolled inflammation or due to failure of the immune system?
bacteria GENETIC POLYMORPHISMS
fungi, viruses
Renal failure
D
parasites
SIRS Lung failure Liver failure E
LIR SIRS altered CNS failure A
organ Cardio Heme failure
When perfusion vascular T
focus microorganisms invade,
failure
multiply in a sterile site H
D
E
TUMOR NODES METASTASES Death
A
T
H

Site of D
infection
SEVERE ARDS E
Local SEPSIS MOFS
infection
SEPSIS SEPTIC A
Characteristics
of the particular
SHOCK T
pathogen
H
Clinical presentation of sepsis
A disorder due to uncontrolled inflammation ? Or due to failure of the immune system?
 Mortality Increases in Septic Shock
Patients
Incidence Mortality

Sepsis
400,000 7-17%

Severe Sepsis 20-53%

300,000

Approximately 200,000 Septic

53-63%
patients including 70,000 Shock
Medicare patients have
septic shock annually

Balk, R.A. Crit Care Clin 2000;337:52

Dear SIRS I don’t like you...
Definitions Cont.
 Differential Diagnosis

• Pancreatitis
• Ischeamic Gut
• Hypovolaemic shock
– GI bleed / AAA rupture / ectopic / dehydration
• Cardiogenic shock
– AMI / Myocarditis / Tamponade
• PE
• Toxic Shock Syndromes
– Staph Aureus
– Group A Strep
• Addisonian crisis (note relative adrenocorticoid insufficiency in many
septic patients)
• Thyroid Storm
• Toxidromes
– Anticholinergic / serotoninergic
 Investigations
• Basic • Specific ?Source
• WBC • Urine
• Platelets • CxR
• Coags • Blood Cultures x 2
• Renal function • LP
• Glucose • Aspirate
• Albumin • Biopsy
• LFT May all be normal early on!
• ABG
 Clinical progression and
laboratory results
• Patient’s fever persists to hospital Day 7
and he develops new pulmonary infiltrates
• Blood pressure remains stable
• Peripheral WBC count increases to
18.2 x 109/L (18 200/µL) with 50% mature
polymorphonuclear leukocytes and
30% bands
Comorbid disease and immunosuppression-chronological vs biological age-population health:
* socio economic factors
Stressor cultural influences
environmental influences
Physiologic Event diet, exercise, employment
employmen
Reserve meas
mea ure
sure d Disease process
alcohol, smoking
Massive hemorrhage
genetic severity
severity Trauma
environmental Burns
factors that
RISKOF
RISK OF
Major operations
contribute to OUTCOME Infections CRITICALILLNESS
CRITICAL ILLNESS

Proactive Reactive •Cell injury

•Dysoxia
Adjunctive Supportive diagnosis
Inappropriate statistical
methods, poor selection of
patients

THERAPY Assessment of specific therapy:

Cardiovascular reserve Errors antibiotics, timely surgery,
Immune state Complications thrombolytics, insulin
Inflammatory response
Nutrition
Potential links between
Cardiovascular reserve and Assessment of supportive
Inflammatory response management:
OUTCOME hemodynamics, ventilation, dialysis
FAILURE TO SHOW CONVINCINGLY Which? Variability in supportive management
FAILURE TO SHOW CONVINCINGLY Inappropriate use of mortality
COMPARABILITY BETWEEN PATIENTS
COMPARABILITY BETWEEN PATIENTS End point for both supportive and specific therapy
CRITICAL CARE STUDIES:
CRITICAL CARE STUDIES:
REDEFINING THE RULES
 Key learning points

• It is important to select appropriate antibiotics

• Administer antibiotics at the right dose for the
appropriate duration
• Cultures should be obtained to confirm the
microbiological diagnosis — nosocomial
pathogens not previously encountered may cause
infections
THE EARLIEST , THE BETTER
>3 risk factors and symptoms 2 or more Candida positive foci
HIGH RISK
PATIENT

Peritoneal infection
Candida in the blood
Candida endophtalmitis
Urinary tract infection
Candida in Candiduria
peritoneal with leukocyturia >105mL
cavity
+drainage
cultures
Pancreas
liver pancreatitis spleen

>104
BAL Cultures of
>103 Pleural fluid
PBS Pericardial
abnormal fluid,
Tipical Ct scan Signs and symptoms chest BAL,
of infection and organ radiograph Tracheal
findings dysfunction
aspirate

Certain infection Suspected infection

Prophylaxis therapy Definite therapy Early pre-emptive/empiric therapy
“MORE IS MISSED BY NOT LOOKING
THAN BY NOT KNOWING”
Anonymous

Patient examination in the Intensive Care Unit

THE INITIAL EXAMINATION
THE PHYSICAL EXAMINATION
•Neurological
•Airway
•Breathing
•Cardiovascular system
•Gastrointestinal system Guidelines for daily recording of
•Renal system and fluids patient’s clinical status
•Limbs
•A airway
•B breathing
•C circulation
•D disability – GCS and focal neurology
•E electrolytes – results
•F fluids – are they appropriate?
•G gut- examine (IAP) and nutritional assessment
•H ematology
•I infection – microbiology and WC count, procalcitonin , CRP
•L lines – are the sites clean ? How long have they been in ?
•M medications- review and interactions
•R relatives – what is the common message ?
•S skin
 MOST COMMON SIGNS OF SEPSIS
• Fever (sometimes hypothermia), chills
• Increased serum concentration of C reactive protein (CRP) and
procalcitonin (PCT), altered white blood cell count, increased interleukin 6
(IL-6), IL-8……
• Increased heart rate, increased cardiac output, low systemic vascular
resistance, increased oxygen consumption, low oxygen extraction ratio (OER)
• Tachypnea, low PaO2/FiO2
• Altered skin perfusion, reduced urine output
• alterations in coagulation parameters, increases D-dimers, low protein C , low
antithrombin, increased prothrombin time/activated partial thromboplastin
time
• Increased insulin requirements
• unexplained alterations in mental status
• Increased urea and creatinine, low platelet count or other coagulation
abnormalities, hyperbilirubinemia

Vincent JL: “Sepsis definitions” Lancet Infect Dis 2002, 2:135

 Cytokines Kinetics
8000

7000

6000
TNF
5000 IL-6
sEselectin
4000 PCT
CRP
3000 Neopterin
LBP
2000

1000

0
0 1 2 3 4 5 10 25 30 50 70 HOURS
 Endotracheal increasing decreasing
tube costs and CASS
evidence
resource or
utilization
Kinetic rx acceptance
Subglottic
secretions BIPAP/HME

Oral care/oral intubation

Endotracheal
Avoid sedation/Infection control
tube cuff
Wean/semirecumbent/condensate
biofilm removal/avoid gastric overdistension

Pooled Dispersal of
secretions biofilm
in airway with ventilation
•Kinetic rx= kinetic therapy
•CASS= Coninuous aspiration subglottic space
 Treatment
• Specific
– Antibiotics
• Empiric based on source
• Know local pathogens
• Use the RMO guidelines / pharmacy handbook for best
guess treatment
• Ideal to get cultures 1st but do not delay antibiotics
– Surgery
• Get the pus out! All of it!
• Early definitive care will improve survival
 Treatment
• Supportive
– Oxygenate / Ventilate (6ml/kg)

– Volume
• Will need more than ‘maintenance’ + replace losses with like fluid
• Colloid v Chrystalloid (SAFE trial awaited – know the results!)

– Inotropes
• Noradrenalin is inotrope of choice, dopamine next

– Early ICU referral

 Treatment

• Supportive

– Electrolyte homeostasis
• THAM for pH <7.2 1-2mL / kg over 20min

– Address co-morbidities
• ß-Blocker & reduced inotropy
• DM / COAD
• Alcoholism / malnutrition / steroids
• Stop nephrotoxins (NSAIDs)

– Early ICU referral

 ANTIBIOTICS IN SEPSIS 1
•Retrospective studies have shown that early administration of
appropriate antibiotics reduces the mortality in patients with
bloodstream infections caused by Gram-negative bacteria

•Antifungal therapy is recommended for patients with candidemia.

Whether early treatment is associated with better outcome is
unknown, and additional studies are needed to evaluate this
question
 ANTIBIOTICS IN SEPSIS 2

Monotherapy with carbapenem antibiotics= β-lactam and an

aminoglycoside (Netspan)

Extended spectrum carboxypenicillins or ureidopenicillins combined

with beta lactamase inhibitors (Tazact) have been shown to be
effective for the treatment of suspected infections in febrile ,
neutropenic cancer patients and in patients with peritonitis or
nosocomial pneumonia.

Monotherapy with aztreonam appears to be as effective as

combination of a beta lactam and an aminoglycoside(Netspan)
for the treatment of patients with documented Gram negative
sepsis
 TREATMENT OPTIONS FOR INFECTIONS DUE TO
EXTENDED –SPECTRUM β-LACTAMASE (ESBL)
PRODUCING ORGANISMS
FIRST CHOICE SECOND CHOICE
Urinary tract infection QUINOLONE Amoxycillin/clavulanate
Ventilator-associated CARBAPENEM/betala Quinolone
pneumonia ctam-beta-lactamase
inhibitor
combination(TAZACT)
Bacteremia CARBAPENEM Quinolone
(imipenem or
meropenem)
Intra-abdominal CARBAPENEM Quinolone
infection

Post-neurosurgical MEROPENEM ? Cefepime (in very high dose)

meningitis
 Possible empiric antibiotic choice in severe sepsis
Suspected site of infection antibiotic
Pneumonia Cefotaxime + erythromicin
Community acquired Cefotaxime/ceftazidime alone or
Hospital acquired Ureidopenicillin + aminoglycoside
VAP Carbapenem , quinolone
Urinary trait Quinolone
Community acquired Amoxicillin + clavulanic acid (co-amoxiclav)
Hospital acquired Ceftazidime alone or
Ureidopenicillin + aminoglycoside
Skin and soft tissue Benzyl-penicillin + nafcillin (flucloxacillin)
Community acquired Cefotaxime + nafcillin or
Hospital acquired Cefotaxime + vancomycin
Intra-abdominal Cefotaxime + metronidazole or
Ureidopenicillin + aminoglycoside or
Carbapenem (monotherapy), quinolone
Biliary tract Ureidopenicillin + aminoglycoside
Neutropenic Ureidopenicillin + aminoglycoside or
Ceftazidime monotherapy
Nosocomial severe sepsis and septic shock without a clear site of infection:
Beta lactam + vancomycin + aminoglycoside or quinolone
 CONCENTRATION
CONCENTRATION DEPENDENT
DEPENDENT vs
vs INDEPENDENT
INDEPENDENT BEHAVIOR
BEHAVIOR OF
OF ANTIBIOTICS
ANTIBIOTICS

•• CONCENTRATION
CONCENTRATION DEPENDENT DEPENDENT (TIME (TIME INDEPENDENT)
INDEPENDENT)
•• The
The rate
rate and extent ofof bacterial
bacterial kill and
and the PAE
PAE all
all increase
increase as
as the
the antibiotic
antibiotic
concentration
concentration increase
increase
•• A)
A) aminoglycosides
aminoglycosides
•• B)
B) fluoroquinolones
fluoroquinolones
•• C)
C) metronidazole
metronidazole
•• CONCENTRATION
CONCENTRATION INDEPENDENTINDEPENDENT (TIME (TIME DEPENDENT)
DEPENDENT)
•• Once
Once aa threshold
threshold concentration
concentration of of these
these antibiotics
antibiotics is achieved
achieved , further
further
increases
increases in
in antibiotic
antibiotic concentration
concentration do do not
not result
result in
in an
an appreciably
appreciably increased
increased
rate
rate or
or extent
extent of
of bacterial
bacterial kill
kill or
or an
an extension
extension of
of the
the PAE
PAE
•• A)
A) β-lactam
β-lactam antibiotics
antibiotics
•• B)
B) vancomycin
vancomycin
•• C)
C) Monobactam
Monobactam (aztreonam) ?
•• D)
D) Carbapenem
Carbapenem (imipenem) ?
 I.M. I.V. P.O. In vivo host, pathogen and
antibiotic factors that may
Altered
Tissue influence the antimicrobial
absorption
perfusion effect at the site of infection
CENTRAL COMPARTMENT
(plasma)

hypometabolic Drug distribution

elimination Protein binding
hypermetabolic
elimination Bacterial pathogen
Site of infection •Inoculum
•Growth phase
Immune Intracellular
penetration •Glycocalyx
function Extracellular
•Intra/extracellular

fluid cells
Y Y Y

Y Y

Y
Cellular compartment

•Oxygen tension
Environmental factors •Ion concentration
•pH
 Biofilm , Antimicrobial Resistance and Infections
Stimulation
Stimulation of of Staphylococcus
Staphylococcus epidermidis
epidermidis growth
growth andand biofilm
biofilm formation
formation byby catecholamine
catecholamine inotropes
inotropes
The
The ability
ability of
of catecholamine
catecholamine inotropic
inotropic drugs
drugs to
to stimulate
stimulate bacterial
bacterial proliferation
proliferation and
and biofilm
biofilm formation
formation may
may
be
be an
an aetiological
aetiological factor
factor in
in the
the development
development of of intravascular
intravascular catheter
catheter colonisation
colonisation and
and catheter
catheter related
related
infection.
infection. The
The removal
removal ofof iron
iron from
from trasferrin
trasferrin for
for subsequent
subsequent use
use by
by S.
S. epidermidis
epidermidis isis aa possible
possible
mechanism
mechanism by by which
which catecholamine
catecholamine inotropes
inotropes stimulate
stimulate bacterial
bacterial growth
growth as
as biofilms
biofilms
Lancet
Lancet 2003;
2003; 361:130-135
361:130-135
Singh
Singh PK,
PK, Parsek
Parsek MR,
MR, Greenberg
Greenberg EP,
EP, Welsh
Welsh MJ
MJ AA component
component of
of innate
innate immunity
immunity prevents
prevents bacterial
bacterial biofilm
biofilm development
development .. Nature
Nature 2002;
2002; 417:552-5
417:552-5
Drenkard
Drenkard E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3
E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3

Planktonic growth QS QS

QS

Pili
Flagell Quorum Sensors QS
a (homoserine lactones)
Antibiotic susceptibility Proteases
Hemolysins
Transcriptional ExotoxinA
ANTIBIOTIC RESISTANCE activators Pyocyanin
LasR Superoxide dismutase
RhIR Catalase
 Mortality with and without appropriate antibiotics

Mortality with Mortality without

appropriate appropriate
antibiotics antibiotics
Category of underlying n % n % P
diseases
Rapidly fatal 82/98 84 34/40 85 NS

Ultimately fatal 124/289 42 64/96 67 <0.001

Nonfatal 50/506 10 44/152 2 <0.001

Total 256/902 28 142/288 49 <0.001

Pierre Yves Bochem Intensive Care Med (2001) 27

 100

90

80

70

60
inad/treat
50
hosp/mort
40

30

20

10

0
VRE CANDIDA ORS A CNS P.aerugin klebsiel Enterococ E.coli OS S A

Hospital mortality and rates of inadequate antimicrobial

treatment according to the most common pathogens associated
with bloodstrem infections. OSSA= oxacillin sensitive S aureus;
CNS= coagulase negative staphylococci; VRE= vancomycin
resistant enterococci
Chest 2000; 118:146-155
 Infection:certain
Infection: certainor
orsuspected
suspected
Prophylactic
PRECAUTIONARY

therapy DEFINITIVEANTIBIOTIC
DEFINITIVE ANTIBIOTIC
Microbiological monitoring TREATMENT** **
THERAPY

TREATMENT
•Antibiogram
•Antibiogram
Pre-emptive •MIC
•MIC
EMPIRICANTIBIOTIC
EMPIRIC ANTIBIOTICTHERAPY
THERAPY
therapy •Antibioticserum
•Antibiotic serumconcentration
concentration
(peakand
(peak andthrough)
through)
/MIC18>125%
•AUC24/MIC
•AUC >125%
24 18

EARLY
EARLY ADEQUATE APPROPRIATE
ADEQUATE APPROPRIATE
**high doses
endovenous bolus
high peak concentration
polychemotherapy
rotation therapy
Primary cofactor Bacterical and 3 days and reassess
Way of treatment
Early start of fungine epidemiology appropriate inappropriate
chemotherapy of that specific ICU
(no more than 6hrs
from the admittance) Inadequate Adequate
SUCCESS
52.5% 47.5%

Failure Failure
23.3% 5.7%
FAILURE
OPTIMALANTIBIOTIC
OPTIMAL ANTIBIOTICTHERAPY
THERAPYIN
INICU
ICU
 Aztreonam
Piperacillin
Mezlocillin
Immunocompromised Imipenem
and at septicaemia Meropenem
lower Host + Infection Mecillinam
concentration Cefepime
Cefuroxime
Ceftazidime
Cefotaxime
Inadequate antibiotic therapy PBP2
PBP3 (e.g. penicillin binding protein (PBP)-2 and 3 specific)

Conversion of bacilli
Induction of filamentous bacterial forms to round, spheroidal cells

Intermediate
High bacterial mass
endotoxin release

High endotoxin release Low endotoxin release

Tobramycin,Amikacin
SEPTIC SHOCK
Other factors Gentamicin,Polymyxins
Teicoplanim,Vancomycin
Ciprofloxacin,Moxifloxacin
 SCREEN PROPHYLAXIS
In high risk patient
* Hemocultures *oral
*Colonization index nasogastric
*Signs and symptoms of sepsis Nystatin
Fluconazole
*Yoghurt
Positive Negative
+ Fungal hemocultures Fungal hemocultures -

SICK
SICK NOT SICK NOT SICK NOT SEPTIC

Assess Surveillance:
OK clinical Hemocultures
SEPTIC scenario plus SEPTIC
Colonization index

Removal of catheters
Removal of catheters bacterical
To treat? =To treat >2 sites or clinical or
Antifungal therapy sterile site positive. sepsis plus
Know the fungal species Sepsis in spite of 2 sites
Prophylaxis antibiotics
and antibiogram (MIC) with
Fluconazole or Ambisome or high dose probably
Caspofungin or both fluconazole Treat like candida treatment
TO PRESERVE VITAL ORGAN PERFUSION AND TO
MAINTAIN TISSUE OXYGENATION

• SUPPORTIVE THERAPY
- Haemodynamic support
Early goal directed therapy
- Respiratory support
Protective ventilation strategy

• MANAGEMENT OF COAGULOPATHY
 Supplemental oxygen +/- Rivers E et al
Endotracheal intubation and
Mechanical ventilation “EGDT in the treatment
of severe sepsis and
Central venous and
septic shock”
Arterial catheterization N Engl J Med 2001,
345:1368-1377
Sedation,paralysis
(if intubated)
Or both
crystalloid
CVP
8-12 mmHg
<65mmHg colloid
MAP >90mmHg Vasoactive agents
>65 and<90mmHg
ScvO2
<70% Transfusion of red cells >70%
Until hematocrit>30% <70%
>70%
Inotropic agents
NO Goals
achieved
YES
ICU admission
 Clinical diagnosis
of ALI

If If
150 > PaO2/FiO2 >100 PaO2/FiO2 < 100

Colloids and Colloids and Colloids and

diuresis CVVH CVVH
 THE KIDNEY IN SEPSIS
• Renal failure developing in the ICU carries a poor prognosis while
combined renal and respiratory failure carries a considerably worse
prognosis than respiratory failure alone
• In the absence of disease modifying therapies, it is impossible to
measure the impact on mortality for preventing acute renal failure
• Renal salvage with furosemide, while having some theoretical benefits
on reducing tubular cell energy consumption and flushing of debris out
of tubules and ducts, has never been shown convincingly to improve
either renal function or survival
• Similarly , the use of dopamine to increase renal flow is probably not
advantageous and may be detrimental

•• De
De Mendoca
Mendoca A,Vincent
A,Vincent JL,Suter
JL,Suter PM
PM et
et al
al (2000)
(2000) Acute
Acute renal
renal failure
failure in
in the
the ICU:risk
ICU:risk factors
factors and
and outcome
outcome evaluated
evaluated byby the
the SOFA
SOFA score.
score. Intensive
Intensive Care
Care
Med 26:915-921
Med 26:915-921
•• Sweet
Sweet SJ,
SJ, Glenney
Glenney CU,CU, Fitzgibbons
Fitzgibbons JP,
JP, Friedman
Friedman P, P, Teres
Teres D D (1981)
(1981) Synergistic
Synergistic effect
effect of
of acute
acute renal
renal failure
failure and
and respiratory
respiratory failure
failure in
in the
the surgical
surgical
intensive
intensive care
care unit.
unit. Am
Am JJ Surg
Surg 141:492-496
141:492-496
•• Brezis
Brezis M,
M, Agmon
Agmon Y, Y, Epstein
Epstein FH
FH (1994)
(1994) Determinants
Determinants of of intrarenal
intrarenal oxygenation.
oxygenation. I.I. Effects
Effects ofof diuretics.
diuretics. Am
Am JJ Physiol
Physiol 267:
267: F1059-F1062
F1059-F1062
•• Bellomo
Bellomo R,R, Chapman
Chapman M, M, Finfer
Finfer S,
S, Hicking
Hicking K,K, Myburgh
Myburgh JJ (2000)
(2000) Low
Low dose
dose dopamine
dopamine inin pazienta
pazienta with
with early
early renal
renal dysfunction:
dysfunction: aa placebo
placebo controlled
controlled
randomized
randomized trial.
trial. Australian
Australian and
and New
New Zealand
Zealand Intensive
Intensive Care
Care Society
Society (ANZIC)
(ANZIC) Clinical
Clinical Trial
Trial Group.
Group. Lancet
Lancet 356:2139-2143
356:2139-2143
•• Galley
Galley HF
HF (2000)
(2000) Renal
Renal dose
dose dopamine:
dopamine: will
will the
the message
message nownow getget through?
through? Lancet
Lancet 356:2112-2113
356:2112-2113
Administration of low dose dopamine by
continuous intravenous infusion (2μg/Kg/min/)
to critically ill patients at risk of renal failure
does not confer clinically significant protection
from renal dysfunction
Low dose dopamine in patients with early renal dysfunction: A placebo controlled randomized trial (ANZICS clinical trials group)
Lancet 2000; 356:2139-43

low dose of dopamine is thought to be harmless.

That is not true.
DOPAMINE:
* suppress respiratory drive * increase cardiac output
* increase myocardial VO2 * trigger myocardial ischaemia, arrhytmias
* induce hypokalaemia, hypophosphataemia * predispose to gut ischaemia
* disrupt metabolic, immunological homoeostasis (action on T cells function)
There is no justification for using “renal dose”
dopamine in the critically ill
A B C
Normal nonstressed Normal function of the Corticosteroid
function of the hypothalamic- hypothalamic-pituitary- insufficiency during
pituitary-adrenal axis adrenal axis during illness acute illness
Central nervous
Reduced + system disease,
Hypothalamus
- feedback - corticosteroids
Stress
CTRH+ -
CTRH + CTRH++ cytokines
Pituitary apoplexy,
Pitutary - - - corticosteroids
-
ACTH + ACTH++ ACTH+ Cytokines,

- anesthetics
antiinfective agents
corticosteroids
Adrenal hemorrage,
infection

Increased cortisol and Decreased cortisol and

Binding of cortisol
decreased corticosteroid Decreased corticosteroid
to corticosteroid
binding globulin Binding globulin
binding globulin
Cytokines,local Cytokines
corticosteroid Glucocorticoid
activation resistance -
Normal action Increased action + Decreased action
in tissue in tissue in tissue
Activity of the Hypothalamic-Pitutary-Adrenal Axis under Normal Conditions (A), during an
Appropriate Response to Stress (B) and during an Inappropriate Response to Critical Illness ( C )
 Potential effetcs of corticosteroids
during septic shock
Activation of IKB-
Correction of a Inhibition of NFk- Decreased
relative trascription for
adrenocortical proinflammatory
deficiency cytokines, Cox-
Reversal of adrenergic 2, ICAM-1,
receptor desensitization VCAM-1.
Inhibition of deficiency
inducible Increased
iNOS transcription
Hemodynamic for IL-1-RA
improvement

Decrease in the dosage

of catecholamines
 Nonresolving acute Critical illness
respiratory distress (especially if features of corticosteroids
syndrome insufficiecy are present

Randomly, timed measurement

THE SCHEME of cortisol level
HAS BEEN EVALUATED
FOR PATIENTS
WITH SEPTIC SHOCK
Annane et al. <15μg/dl 15-34μg/dl >34μg/dl
JAMA 2000
283:1038-1045
Increase in response
Annane et al
to corticotropin test
JAMA 2002
288:862-871
<9μg/dl >9μg/dl
Functional
hypoadrenalism
Hypoadrenalism likely
unlikely

Initiate pharmacologic Consider physiologic

Corticosteroid therapy
glucocorticoid Corticosteroid
Unlikely to be helpful
therapy replacement
Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels and
response to the corticotropin stimulation test. It must be borne in mind that no cutoff value will be entirely reliable
 Mild illness or condition Septic shock
Moderate illness or Severe illness or
(nonfebrile cough or cold (cathecolamine
condition(fever, minor condition (major surgery,
Dental extraction with dependency, poor
trauma,minor surgery) trauma, critical illness
Local anesthetic) response to ACTH)

Increase dose to 50 mg of
Increase dose to
15mg Hydrocortisone IV
50mg of
of prednisolone/day Every 6 hr with
Hydrocortisone
or or without 50μg of
IM or IV every 6 hr
equivalent Fludrocortisone/ day

Return to normal Taper dose to normal

No change dose 24 hr after by decreasing by Treat for 7 days
resolution 50% per day

Suggested corticosteroid replacement doses during intercurrent and acute illness in patients
with proven or suspected adrenal insufficiency, including those receiving corticosteroid therapy
OTHER SUPPORTIVE THERAPY IN SEPSIS 1

Deep Vein Thrombosis (DVT) in septic patients and the

high percentage of sepsis /infected patients included in studies
that have demonstrated efficacy of DVT prophylaxis in general,
septic patients should be treated with DVT prophylaxis. Even
though there is not a randomized study that establishes the
impact of DVT prophylaxis on morbidity and mortality
specifically in septic patients, the significant number of septic
patients included in the populations of patients enrolled in other
prospective randomized trials supports that the use of DVT
prophylaxis reduces morbidity and mortality in septic patients.
 Glycogen COUNTER REGULATORY
COUNTER REGULATORY
HORMONES
Glucose HORMONES
CYTOKINES
CYTOKINES
STRESS
Pyruvate STRESS
Alanine
Glycolysis
LIVER
Glucose
Gluconeogenesis Glucose Pyruvate glycogen
Lactate
Lactate Alanine
Alanine
Lactate
Glycolysis
pyruvate

Glycerol Amino
Proteinolysis
acids

Lipolysis
 High risk patient
APACHE II >25

Fever
BP Oxygenation BP Oxygenation
symptoms
Tachycardi Oliguria
a
Tachypnea
INFECTION SEPSIS SEVERE SEPSIS SEPTIC SHOCK MODS
Specific Empiric ?
care antibiotic therapy Drotecogin α (activated)
Source control
Cultures,source
Cultures, sourcecontrol
control, , antibiotics,
antibiotics, intensiveinsulin
intensive insulin therapy
therapy

Supportive *Fluids *oxygen therapy * vasopressors *mechanical

care *EGDT *pressure support * inotropes ventilation
ventilation * moderate *low TV
*NIV corticosteroids *recruitment
* vasopressin manovreus
*prone
position
*CVVH etc
 Conceptual models of multiple organ dysfunction syndrome
Pathologic process
Uncontrolled infection, occult
poorly controlled infections
(pneumonia, peritonitis)
Systemic inflammation (SIRS)
Immune paralysis
Tissue hypoxia
Microvascular coagulopathy and
endothelial activation
Dysregulated apoptosis
Gut liver axis
Metabolic,endocrine dysfunction
Manifestations of MODS
Persistent infection, nosocomial ICU
acquired infection, endotoxemia
Cytokinemia (particularly IL-6,IL-8,TNF),
leukocytosis, increased capillary
permeability: edema
Nosocomial infection, increased anti-
inflammatory cytokine levels (IL-10),
decreased HLA-DR expression
Increased lactate
Increased procoagulant activity, decreased
anticoagulant activity, increased von
Willebrand factor, soluble
thrombomodulin; increased capillary
permeability
Increased epithelial and lymphoid apoptosis
(gut and spleen), decreased neutrophil
apoptosis
Increased infection with gut organisms
(translocation?) endotoxemia, Kupffer cell
activation, spill over
Hyperglicemia,relative adrenal
insufficiency, hypothyroidism
Therapeutic Implications
Aggressive (?!) use of antibiotics and
source control measure
Neutralization of specific cytokines
(IL-1, TNF, PAF) or of activational
pathways (afelimomab when IL-6 )
G-CSF, interferon gamma
Augmentation of DO2 (early
optimization of DO2 and SvO2)
Augmentation of anticoagulant
mechanisms (APC-Prowess trial !,
AT-Kybersept trial ? TFPI ?)
Caspase inhibition
Anti-oxidants
Selective digestive tract
decontamination, enteral feeding,
immunenutrition, reconditioning of
the gut flora
Strict control of glycemia,
coticosteroids in stress doses in septic
 Novel Therapies
Summary
Reducing mortality in sepsis: new directions
• This is highly recommended reading, concise reviews of
– Low tidal volume ventilation
– Early goal directed therapy
– Drotrecogin alfa (activated)
– Moderate dose corticosteroids
– Tight control of blood sugar

Critical Care 2002, 6(Suppl 3):S1-S18 (http://ccforum.com/content/6/S3/S1 )

 Novel Therapies
• NAC Crit. Care. Med. 2003 31 (11) 2574-78
– Nuclear factor-κB controls expression
inflammatory mediators
– NAC inhibits NFKB in vitro
– Pilot trial
• 20 patients, randomised
• 72 hrs NAC or placebo
• IL-8 suppressed (may be implicated in lung injury)
• Recommend larger human trials
 Summary
• Sepsis may be obvious or subtle early
• There is a high mortality and morbidity
• Have a high index of suspicion
• Know local organisms / susceptibilities
• Take appropriate cultures
• Treat early and aggressively
• Investigate early and aggressively
• Refer early and aggressively
• Be aware of new developments