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

356

358

360

362

364

366

368

370

372

374

1988 1989 1990 1991 1992 1993 1994 1995

Mea

n n

o o

f h

osp

ital

bed

s

36

38

40

42

44

46

48

50

Mea

n n

o o

f IC

U b

eds

Clin Infect Dis 1997;24:211-215Seminars in Respiratory and critical care med 2003,24(1):3-22,

Though ICUs account for only 8% of hospital beds,

45% of infections in a hospital originate in an ICU

Distribution of major sites of infection in medical ICU’s

5%5%

6%

30%

30%

16%

3% 3%

CVS GI LRI PN UTI BSI SST EENT

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

Nosocomial troika ……..

• S.aureus

• E.coli

• Pseudomonas aeruginosa

extended

•K.Pneumoniae

•Enterobacteriaceae

•Citrobacter fruendii

Eight most common pathogens associated with nosocomial infection in an ICU, NNIS January 1989 - July 1998

All sites n=235,758

BSI n=50,091

PNEU n=64,056

UTI n=47,502

SSI n=22,043

Others n=52,066

Coagulase negative staphylococci

14.3 39.3 2.5 3.1 13.5 15.4

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 Albicans

6.6 4.9 4.0 15.3 4.8 4.3

Klebsiella Pneumoniae

4.7 2.9 6.5 6.1 3.5 3.5

Clinics in Chest Medicine 1999; Vol 20: No: 2,JAC 2003; 51, Suppl S2, 115-117

High Risk Patients• For Sepsis– 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

A clinical response arising from a nonspecific insult, including 2 of the following:

• Temperature 38oC or 36oC• HR 90 beats/min• Respirations 20/min• WBC count 12,000/mm3 or

4,000/mm3 or >10% immature neutrophils

SIRS = Systemic Inflammatory Response Syndrome

SIRS with a presumed or confirmed infectious process

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

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

Sepsis: Defining a Disease Continuum

Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Sepsis with 1 sign of organ failure

Cardiovascular (refractory hypotension)

RenalRespiratoryHepaticHematologicCNSMetabolic acidosis

ShockShock

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 infectionPathophysiology : a continuum

A disorder due to uncontrolled inflammation or due to failure of the immune system?

Clinical presentation of sepsisA disorder due to uncontrolled inflammation ? Or due to failure of the immune system?

LIRLIR

LocalinfectionLocalinfection

SIRSSIRS

SEPSISSEPSIS

SIRSalteredorganperfusion

SIRSalteredorganperfusion

SEVERESEPSISSEVERESEPSIS

Lung failureLung failure

Cardiovascularfailure

Cardiovascularfailure

ARDSARDS

SEPTICSHOCKSEPTICSHOCK

Renal failureLiver failureCNS failureHeme failure

Renal failureLiver failureCNS failureHeme failure

MOFSMOFS

DEATH

DEATH

DEATH

DEATH

bacteria fungi, viruses parasites

bacteria fungi, viruses parasites

focusWhenmicroorganisms invade,multiply in a sterile site

Whenmicroorganisms invade,multiply in a sterile site

Site ofinfection

TUMORTUMOR NODES METASTASESDEATH

DeathDeath

Characteristicsof the particular

pathogen

GENETIC POLYMORPHISMS

Mortality

Septic Shock

53-63%

20-53%Severe Sepsis300,000

7-17%Sepsis

400,000

Incidence

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

Mortality Increases in Septic Shock Patients

Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually

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• WBC

• Platelets

• Coags

• Renal function

• Glucose

• Albumin

• LFT

• ABG

• Specific ?Source• Urine

• CxR

• Blood Cultures x 2

• LP

• Aspirate

• Biopsy

May all be normal early on!

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

measuredseveritymeasuredseverity

OUTCOMEOUTCOME

PhysiologicReservegeneticenvironmentalfactors thatcontribute to

PhysiologicReservegeneticenvironmentalfactors thatcontribute to

Stressor EventDisease processMassive hemorrhageTraumaBurnsMajor operations

Infections

Stressor EventDisease processMassive hemorrhageTraumaBurnsMajor operations

InfectionsProactiveAdjunctive ProactiveAdjunctive

ReactiveSupportive ReactiveSupportive

THERAPYErrorsComplications

THERAPYErrorsComplications

Comorbid disease and immunosuppression-chronological vs biological age-population health: * socio economic factors cultural influences environmental influences diet, exercise, employment alcohol, smoking

Comorbid disease and immunosuppression-chronological vs biological age-population health: * socio economic factors cultural influences environmental influences diet, exercise, employment alcohol, smoking

Inappropriate statisticalmethods, poor selection ofpatients

Inappropriate statisticalmethods, poor selection ofpatients

Assessment of specific therapy:antibiotics, timely surgery, thrombolytics, insulin

Assessment of specific therapy:antibiotics, timely surgery, thrombolytics, insulin

Assessment of supportive management:hemodynamics, ventilation, dialysisVariability in supportive management

Assessment of supportive management:hemodynamics, ventilation, dialysisVariability in supportive management

Cardiovascular reserveImmune stateInflammatory responseNutritionPotential links between Cardiovascular reserve andInflammatory response

Cardiovascular reserveImmune stateInflammatory responseNutritionPotential links between Cardiovascular reserve andInflammatory response

OUTCOMEWhich?Inappropriate use of mortalityEnd point for both supportive and specific therapy

OUTCOMEWhich?Inappropriate use of mortalityEnd point for both supportive and specific therapy

RISK OFCRITICAL ILLNESS

RISK OFCRITICAL ILLNESS

FAILURE TO SHOW CONVINCINGLYCOMPARABILITY BETWEEN PATIENTS

CRITICAL CARE STUDIES:

REDEFINING THE RULES

FAILURE TO SHOW CONVINCINGLYCOMPARABILITY BETWEEN PATIENTS

CRITICAL CARE STUDIES:

REDEFINING THE RULES

•Cell injury•Dysoxia diagnosis

•Cell injury•Dysoxia diagnosis

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 BETTERTHE EARLIEST , THE BETTER

Candida endophtalmitis

Urinary tract infectionCandiduria

with leukocyturia >105mL

Pancreaspancreatitisliver

Candida in the bloodPeritoneal infection

Candida inperitoneal

cavity+drainagecultures

HIGH RISKPATIENT

>3 risk factors and symptoms 2 or more Candida positive foci

spleen

Tipical Ct scanfindings

Prophylaxis therapy

Signs and symptomsof infection and organ

dysfunction

Certain infection Suspected infection

Definite therapy Early pre-emptive/empiric therapy

Cultures ofPleural fluidPericardial

fluid,BAL,

Tracheal aspirate

>104

BAL>103

PBSabnormal

chest radiograph

“MORE IS MISSED BY NOT LOOKING THAN BY NOT KNOWING”Anonymous

Patient examination in the Intensive Care Unit

“MORE IS MISSED BY NOT LOOKING THAN BY NOT KNOWING”Anonymous

Patient examination in the Intensive Care Unit

THE INITIAL EXAMINATIONTHE INITIAL EXAMINATIONTHE PHYSICAL EXAMINATION•Neurological•Airway•Breathing•Cardiovascular system•Gastrointestinal system•Renal system and fluids•Limbs

THE PHYSICAL EXAMINATION•Neurological•Airway•Breathing•Cardiovascular system•Gastrointestinal system•Renal system and fluids•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

•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

Guidelines for daily recording of patient’s clinical statusGuidelines for daily recording of patient’s clinical status

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 KineticsCytokines Kinetics

0

1000

2000

3000

4000

5000

6000

7000

8000

0 1 2 3 4 5 10 25 30 50 70

TNFIL-6sEselectinPCTCRPNeopterinLBP

HOURS

Dispersal of biofilm with ventilation

Dispersal of biofilm with ventilation

Pooled secretionsin airway

Pooled secretionsin airway

Endotrachealtube cuffEndotrachealtube cuff

SubglotticsecretionsSubglotticsecretions

Endotracheal tubeEndotracheal tube

biofilmbiofilmWean/semirecumbent/condensateremoval/avoid gastric overdistensionWean/semirecumbent/condensateremoval/avoid gastric overdistension

Avoid sedation/Infection controlAvoid sedation/Infection control

Oral care/oral intubationOral care/oral intubation

BIPAP/HMEBIPAP/HME

Kinetic rxKinetic rx

CASSCASS

increasingcosts andresource

utilization

decreasingevidence

or acceptance

•Kinetic rx= kinetic therapy•CASS= Coninuous aspiration subglottic space•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 TOEXTENDED –SPECTRUM β-LACTAMASE (ESBL)

PRODUCING ORGANISMS

TREATMENT OPTIONS FOR INFECTIONS DUE TOEXTENDED –SPECTRUM β-LACTAMASE (ESBL)

PRODUCING ORGANISMS

FIRST CHOICE SECOND CHOICE

Urinary tract infection QUINOLONE Amoxycillin/clavulanate

Ventilator-associated

pneumonia

CARBAPENEM/betalactam-beta-lactamase inhibitor combination(TAZACT)

Quinolone

Bacteremia CARBAPENEM (imipenem or meropenem)

Quinolone

Intra-abdominal infection

CARBAPENEM Quinolone

Post-neurosurgical meningitis

MEROPENEM ? Cefepime (in very high dose)

Possible empiric antibiotic choice in severe sepsisPossible empiric antibiotic choice in severe sepsisSuspected site of infection antibiotic

Pneumonia

Community acquired

Hospital acquired

VAP

Cefotaxime + erythromicin

Cefotaxime/ceftazidime alone or

Ureidopenicillin + aminoglycoside

Carbapenem , quinolone

Urinary trait

Community acquired

Hospital acquired

Quinolone

Amoxicillin + clavulanic acid (co-amoxiclav)

Ceftazidime alone or

Ureidopenicillin + aminoglycoside

Skin and soft tissue

Community acquired

Hospital acquired

Benzyl-penicillin + nafcillin (flucloxacillin)

Cefotaxime + nafcillin or

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 Nosocomial severe sepsis and septic shock without a clear site of infection: Beta lactam + vancomycin + aminoglycoside or quinolone

CONCENTRATION DEPENDENT vs INDEPENDENT BEHAVIOR OF ANTIBIOTICSCONCENTRATION DEPENDENT vs INDEPENDENT BEHAVIOR OF ANTIBIOTICS

• CONCENTRATION DEPENDENT (TIME INDEPENDENT)

• The rate and extent of bacterial kill and the PAE all increase as the antibiotic concentration increase

• A) aminoglycosides

• B) fluoroquinolones

• C) metronidazole

• CONCENTRATION INDEPENDENT (TIME DEPENDENT)

• Once a threshold concentration of these antibiotics is achieved , further increases in antibiotic concentration do not result in an appreciably increased rate or extent of bacterial kill or an extension of the PAE

• A) β-lactam antibiotics

• B) vancomycin

• C) Monobactam (aztreonam) ?

• D) Carbapenem (imipenem) ?

• CONCENTRATION DEPENDENT (TIME INDEPENDENT)

• The rate and extent of bacterial kill and the PAE all increase as the antibiotic concentration increase

• A) aminoglycosides

• B) fluoroquinolones

• C) metronidazole

• CONCENTRATION INDEPENDENT (TIME DEPENDENT)

• Once a threshold concentration of these antibiotics is achieved , further increases in antibiotic concentration do not result in an appreciably increased rate or extent of bacterial kill or an extension of the PAE

• A) β-lactam antibiotics

• B) vancomycin

• C) Monobactam (aztreonam) ?

• D) Carbapenem (imipenem) ?

Site of infection

Extracellularfluid cells

Cellular compartment

Intracellularpenetration

Environmental factorsEnvironmental factors•Oxygen tension•Ion concentration•pH

•Oxygen tension•Ion concentration•pH

Y Y Y

Y Y

Y

ImmunefunctionImmunefunction

CENTRAL COMPARTMENT(plasma)

CENTRAL COMPARTMENT(plasma)

I.V.I.V. P.O.P.O.

AlteredabsorptionAlteredabsorption

I.M.I.M.

TissueperfusionTissueperfusion

Drug distributionProtein bindingDrug distributionProtein binding

hypermetabolic elimination hypermetabolic elimination

hypometabolic elimination

hypometabolic elimination

Bacterial pathogen•Inoculum•Growth phase•Glycocalyx•Intra/extracellular

Bacterial pathogen•Inoculum•Growth phase•Glycocalyx•Intra/extracellular

In vivo host, pathogen and antibiotic factors that may influence the antimicrobialeffect at the site of infection

In vivo host, pathogen and antibiotic factors that may influence the antimicrobialeffect at the site of infection

Biofilm , Antimicrobial Resistance and InfectionsStimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes

The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter related

infection. The removal of iron from trasferrin for subsequent use by S. epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms

Lancet 2003; 361:130-135Singh PK, Parsek MR, Greenberg EP, Welsh MJ A component of innate immunity prevents bacterial biofilm development . Nature 2002; 417:552-5

Drenkard E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3

Biofilm , Antimicrobial Resistance and InfectionsStimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes

The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter related

infection. The removal of iron from trasferrin for subsequent use by S. epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms

Lancet 2003; 361:130-135Singh PK, Parsek MR, Greenberg EP, Welsh MJ A component of innate immunity prevents bacterial biofilm development . Nature 2002; 417:552-5

Drenkard E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3

Planktonic growthPlanktonic growth

PiliFlagella

PiliFlagella

Antibiotic susceptibilityAntibiotic susceptibility

QSQS

QSQS QSQS

QSQSQuorum Sensors(homoserine lactones)Quorum Sensors(homoserine lactones)

Transcriptional activatorsLasRRhIR

Transcriptional activatorsLasRRhIR

ProteasesHemolysinsExotoxinAPyocyaninSuperoxide dismutaseCatalase

ProteasesHemolysinsExotoxinAPyocyaninSuperoxide dismutaseCatalase

ANTIBIOTIC RESISTANCEANTIBIOTIC RESISTANCE

Mortality with and without appropriate antibioticsMortality with and without appropriate antibiotics

Mortality with appropriate antibiotics

Mortality without appropriate antibiotics

Category of underlying diseases

n % n % P

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

0

10

20

30

40

50

60

70

80

90

100

VRE CANDIDA ORSA CNS P.aerugin klebsiel Enterococ E.coli OSSA

inad/treathosp/mort

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

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 or suspectedInfection: certain or suspected

Microbiological monitoringDEFINITIVE ANTIBIOTIC

TREATMENT **•Antibiogram •MIC •Antibiotic serum concentration

(peak and through)•AUC24/MIC18 >125%

DEFINITIVE ANTIBIOTICTREATMENT **

•Antibiogram •MIC •Antibiotic serum concentration

(peak and through)•AUC24/MIC18 >125%

SUCCESSSUCCESS

FAILUREFAILURE

EMPIRIC ANTIBIOTIC THERAPYEMPIRIC ANTIBIOTIC THERAPY

EARLYEARLY ADEQUATEADEQUATE APPROPRIATEAPPROPRIATE

Way of treatmentWay of treatmentBacterical andfungine epidemiologyof that specific ICU

Bacterical andfungine epidemiologyof that specific ICU

Primary cofactorEarly start ofchemotherapy(no more than 6hrsfrom the admittance)

Primary cofactorEarly start ofchemotherapy(no more than 6hrsfrom the admittance) Inadequate

52.5%Adequate

47.5%

Failure 5.7%Failure 5.7%

Failure 23.3%Failure 23.3%

OPTIMAL ANTIBIOTIC THERAPY IN ICUOPTIMAL ANTIBIOTIC THERAPY IN ICU

appropriate inappropriate

**high doses endovenous bolus high peak concentration polychemotherapy rotation therapy 3 days and reassess

**high doses endovenous bolus high peak concentration polychemotherapy rotation therapy 3 days and reassess

Prophylactictherapy

Pre-emptivetherapy

PR

EC

AU

TIO

NA

RY

TH

ER

AP

Y

ImmunocompromisedHost + Infection

septicaemia

Inadequate antibiotic therapy(e.g. penicillin binding protein (PBP)-2 and 3 specific)PBP3 PBP2

Induction of filamentous bacterial formsConversion of bacilli

to round, spheroidal cells

High bacterial mass

High endotoxin release

SEPTIC SHOCKOther factorsOther factors

AztreonamPiperacillinMezlocillin

and atlower

concentrationCefuroximeCeftazidimeCefotaxime

ImipenemMeropenemMecillinamCefepime

Intermediate endotoxin release

Low endotoxin release

Tobramycin,AmikacinGentamicin,Polymyxins

Teicoplanim,VancomycinCiprofloxacin,Moxifloxacin

SCREEN* Hemocultures

*Colonization index *Signs and symptoms of sepsis

SICK NOT SICK NOT SICK SICK

+ -

SEPTICOK

Removal of cathetersTo treat? =To treat

Removal of cathetersAntifungal therapy

Know the fungal speciesand antibiogram (MIC)

Fluconazole or Ambisome or Caspofungin or both

Prophylaxiswith

high dosefluconazole

SEPTIC

Surveillance:Hemocultures

plusColonization index

>2 sites or clinical or sterile site positive.

Sepsis in spite ofantibiotics

Treat like candida

NOT SEPTIC

bactericalsepsis plus

2 sites

probablytreatment

PROPHYLAXISIn high risk patient

*oralnasogastric

NystatinFluconazole

*Yoghurt

PositiveFungal hemocultures

NegativeFungal hemocultures

Assessclinicalscenario

TO PRESERVE VITAL ORGAN PERFUSION AND TO MAINTAIN TISSUE OXYGENATION

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

• SUPPORTIVE THERAPY

- Haemodynamic support Early goal directed therapy

- Respiratory support Protective ventilation strategy

• MANAGEMENT OF COAGULOPATHY

Supplemental oxygen +/-Endotracheal intubation and

Mechanical ventilation

Central venous and Arterial catheterization

Sedation,paralysis(if intubated)

Or both

CVP

MAP

ScvO2

Goalsachieved

ICU admission

crystalloid

colloid

8-12 mmHg

Vasoactive agents

>65 and<90mmHg

<65mmHg

>90mmHg

Transfusion of red cellsUntil hematocrit>30%

>70%

<70%

Inotropic agents

<70%

>70%

NO

YES

Rivers E et al“EGDT in the treatment of severe sepsis and septic shock”N Engl J Med 2001, 345:1368-1377

Rivers E et al“EGDT in the treatment of severe sepsis and septic shock”N Engl J Med 2001, 345:1368-1377

Clinical diagnosisof ALI

If150 > PaO2/FiO2 >100

IfPaO2/FiO2 < 100

Colloids anddiuresis

Colloids andCVVH

Colloids andCVVH

THE KIDNEY IN SEPSISTHE 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 Mendoca A,Vincent JL,Suter PM et al (2000) Acute renal failure in the ICU:risk factors and outcome evaluated by the SOFA score. Intensive Care Med 26:915-921

• Sweet SJ, Glenney CU, Fitzgibbons JP, Friedman P, Teres D (1981) Synergistic effect of acute renal failure and respiratory failure in the surgical intensive care unit. Am J Surg 141:492-496

• Brezis M, Agmon Y, Epstein FH (1994) Determinants of intrarenal oxygenation. I. Effects of diuretics. Am J Physiol 267: F1059-F1062• Bellomo R, Chapman M, Finfer S, Hicking K, Myburgh J (2000) Low dose dopamine in pazienta with early renal dysfunction: a placebo controlled

randomized trial. Australian and New Zealand Intensive Care Society (ANZIC) Clinical Trial Group. Lancet 356:2139-2143• Galley HF (2000) Renal dose dopamine: will the message now get through? Lancet 356:2112-2113

• 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 Mendoca A,Vincent JL,Suter PM et al (2000) Acute renal failure in the ICU:risk factors and outcome evaluated by the SOFA score. Intensive Care Med 26:915-921

• Sweet SJ, Glenney CU, Fitzgibbons JP, Friedman P, Teres D (1981) Synergistic effect of acute renal failure and respiratory failure in the surgical intensive care unit. Am J Surg 141:492-496

• Brezis M, Agmon Y, Epstein FH (1994) Determinants of intrarenal oxygenation. I. Effects of diuretics. Am J Physiol 267: F1059-F1062• Bellomo R, Chapman M, Finfer S, Hicking K, Myburgh J (2000) Low dose dopamine in pazienta with early renal dysfunction: a placebo controlled

randomized trial. Australian and New Zealand Intensive Care Society (ANZIC) Clinical Trial Group. Lancet 356:2139-2143• Galley HF (2000) Renal dose dopamine: will the message now get through? Lancet 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 dysfunctionLow dose dopamine in patients with early renal dysfunction: A placebo controlled randomized trial (ANZICS clinical trials group)Lancet 2000; 356:2139-43

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 dysfunctionLow 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

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

Normal nonstressedfunction of the hypothalamic-

pituitary-adrenal axis

Normal function of thehypothalamic-pituitary-

adrenal axis during illness

Corticosteroid insufficiency during

acute illness

Binding of cortisolto corticosteroidbinding globulin

Increased cortisol anddecreased corticosteroid

binding globulin

Decreased cortisol andDecreased corticosteroid

Binding globulin

Normal actionin tissue

Increased actionin tissue

Decreased actionin tissue

Hypothalamus Reducedfeedback

Pitutary

Adrenal

CTRH +

ACTH +

-

-

StresscytokinesCTRH++

ACTH++

+

Cytokines,localcorticosteroidactivation

+

-

CTRH+

ACTH+

CytokinesGlucocorticoidresistance -

Central nervoussystem disease,corticosteroids

Pituitary apoplexy,corticosteroids

Cytokines, anestheticsantiinfective agentscorticosteroidshemorrage,infection

-

-

--

-

A B C

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 Potential effetcs of corticosteroids during septic shockduring septic shock

Activation of IKB-

Inhibition of NFk-Correction of a relative adrenocortical deficiency

Reversal of adrenergic receptor desensitization

deficiencyInhibition of inducible iNOS

Hemodynamic improvement

Decrease in the dosage of

catecholamines

Decreased trascription for

proinflammatory cytokines,

Cox-2, ICAM-1, VCAM-1.

Increased transcription for IL-1-RA

Nonresolving acuterespiratory distress

syndrome

Initiate pharmacologicglucocorticoid

therapy

Critical illness(especially if features of corticosteroids

insufficiecy are present

Randomly, timed measurementof cortisol level

<15μg/dl 15-34μg/dl >34μg/dl

Increase in responseto corticotropin test

<9μg/dl >9μg/dl

Hypoadrenalism likely

Functionalhypoadrenalism

unlikely

Consider physiologicCorticosteroidreplacement

Corticosteroid therapyUnlikely to be helpful

Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels andresponse to the corticotropin stimulation test. It must be borne in mind that no cutoff value will be entirely reliable

Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels andresponse to the corticotropin stimulation test. It must be borne in mind that no cutoff value will be entirely reliable

THE SCHEMEHAS BEEN EVALUATED

FOR PATIENTSWITH SEPTIC SHOCK

Annane et al.JAMA 2000

283:1038-1045Annane et alJAMA 2002288:862-871

Mild illness or condition(nonfebrile cough or cold

Dental extraction withLocal anesthetic)

Moderate illness or condition(fever, minor trauma,minor surgery)

Severe illness orcondition (major surgery,

trauma, critical illness

Septic shock(cathecolamine

dependency, poorresponse to ACTH)

Increase dose to 15mg

of prednisolone/day or

equivalent

Increase dose to50mg of

HydrocortisoneIM or IV every 6 hr

50 mg ofHydrocortisone IV

Every 6 hr withor without 50μg of

Fludrocortisone/ day

Return to normaldose 24 hr after

resolution

Taper dose to normalby decreasing by

50% per dayTreat for 7 daysNo change

Suggested corticosteroid replacement doses during intercurrent and acute illness in patientswith proven or suspected adrenal insufficiency, including those receiving corticosteroid therapy

OTHER SUPPORTIVE THERAPY IN SEPSIS 1OTHER 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.

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.

Glycolysis

Proteinolysis

Lipolysis

LactatepyruvateLactatepyruvate

Gluconeogenesis

Glycolysis

Glycerol Glycerol AminoacidsAminoacids

Glucose Lactate Glucose Lactate

Glycogen Glycogen

Glucose Glucose

Pyruvate Pyruvate

Alanine Alanine

Glucose Pyruvate Glucose Pyruvate

Alanine Alanine Lactate Lactate Alanine Alanine

COUNTER REGULATORYHORMONESCYTOKINES

STRESS

COUNTER REGULATORYHORMONESCYTOKINES

STRESS

glycogenglycogen

LIVER LIVER

INFECTION

symptoms

Specific care

Supportivecare

SEPSIS SEVERE SEPSIS SEPTIC SHOCK MODS

BP BP Oxygenation Oxygenation BPBP OxygenationOliguriaOxygenationOliguria

FeverTachycardiaTachypnea

FeverTachycardiaTachypnea

Empiricantibiotic therapySource control

Empiricantibiotic therapySource control

*Fluids *oxygen therapy * vasopressors *mechanical *EGDT *pressure support * inotropes ventilation ventilation * moderate *low TV *NIV corticosteroids *recruitment * vasopressin manovreus *prone position *CVVH etc

*Fluids *oxygen therapy * vasopressors *mechanical *EGDT *pressure support * inotropes ventilation ventilation * moderate *low TV *NIV corticosteroids *recruitment * vasopressin manovreus *prone position *CVVH etc

Drotecogin α (activated)Drotecogin α (activated)

Cultures, source control , antibiotics, intensive insulin therapy Cultures, source control , antibiotics, intensive insulin therapy

?

High risk patientAPACHE II >25High risk patientAPACHE II >25

Conceptual models of multiple organ dysfunction syndromeConceptual models of multiple organ dysfunction syndromePathologic process Manifestations of MODS Therapeutic Implications

Uncontrolled infection, occult poorly controlled infections

(pneumonia, peritonitis)

Persistent infection, nosocomial ICU acquired infection, endotoxemia

Aggressive (?!) use of antibiotics and source control measure

Systemic inflammation (SIRS)

Cytokinemia (particularly IL-6,IL-8,TNF), leukocytosis, increased capillary

permeability: edema

Neutralization of specific cytokines (IL-1, TNF, PAF) or of activational pathways (afelimomab when IL-6 )

Immune paralysis

Nosocomial infection, increased anti-inflammatory cytokine levels (IL-10),

decreased HLA-DR expression G-CSF, interferon gamma

Tissue hypoxia Increased lactate Augmentation of DO2 (early optimization of DO2 and SvO2)

Microvascular coagulopathy and endothelial activation

Increased procoagulant activity, decreased anticoagulant activity, increased von

Willebrand factor, soluble thrombomodulin; increased capillary

permeability

Augmentation of anticoagulant mechanisms (APC-Prowess trial !,

AT-Kybersept trial ? TFPI ?)

Dysregulated apoptosis

Increased epithelial and lymphoid apoptosis (gut and spleen), decreased neutrophil

apoptosis Caspase inhibition

Anti-oxidants

Gut liver axis

Increased infection with gut organisms (translocation?) endotoxemia, Kupffer cell

activation, spill over

Selective digestive tract decontamination, enteral feeding,

immunenutrition, reconditioning of the gut flora

Metabolic,endocrine dysfunction Hyperglicemia,relative adrenal insufficiency, hypothyroidism

Strict control of glycemia, coticosteroids in stress doses in septic shock

Novel TherapiesSummary

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