Gram Negative Sepsis
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Transcript of Gram Negative Sepsis
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
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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