Newer Trends in Sepsis and Septic Shock |

Sepsis is a serious condition in which the body responds improperly to an infection. The infection-fighting processes turn on the body, causing the organs to work poorly. Sepsis may progress to septic shock. This presentation is an overview on "Newer Trends in Sepsis and Septic Shock"

1. Dr. S. K. Jindal
www.jindalchest.com

2. Changing Trends in Sepsis
1.Definitions&Prevalence
2.Riskfactors
3.Pathophysiology
4.Organsystemdysfunction
5.Establishingdiagnosis
6.Treatmentstrategies
7.Futuredirections

3. Definitions
Infection Invasionofsteriletissuebymicroorganism
Bacteremia Viablebacteriainblood
Sepsis Systemicinflammatoryresponse
Severesepsis Sepsisandorgandysfunction
Septicshock Sepsiswithhypotension
Multipleorgan Alteredorganfunctioninseverelysick
dysfunction patients
syndrome

4. Systemic Inflammatory Response
Syndrome
•Inflammatoryresponsetoavarietyofsevereclinicalinsults(vs.sepsis)
•Twoormoreofthefollowing:
Temp >38°Cor<36°C
HR >90beats/min
RR >20breath/minorPaCO
2<32mmHg
WBC >12000/mm
3
or<4000/mm
3
or
10%immaturebandform

5. Clinical Frequency & Mortality (%)
(Mortality included in parentheses)
Study SIRS Sepsis Severe
sepsis
Septic
shock
Rangel Frausto(1995) 68 (7)26 (16)18 (20)4 (46)
Pittet(1995) 93 (6) 49 (0)16 (35)7 (58)
Salvo (1995) 52 (27)5 (36) 2 (52)3 (82)
Saez-Llorem (1995) - 21 (16)61 (40)18 (62)
Proulx(1996) 82 23 4 2
Jones & Lowes (1996)55 (23) 16 5 (38)3 (56)
Muckart (1997) 88 (8)14 (10)14 (18)20 (53)
Bossink (1998) 95 (6)44 (13) - -

6. Risk of Death in First 30 Days
•OverallICU 20%
•Severesepsis 30-50%
•Stroke 12-19%
•Ac.Myocardialinfarction 8%

7. ARDS in Tropics
Infective cause No. of patients
(Mortality)
1. Severe Pneumonia 27(51.8%)
2. Sepsis 25(52.0%)
Immunosuppresivedrugs 9
Post operative 6
Chronic respiatorydisease 3
Neurological 3
Enteric fever 2
Diabetes 2
3. Malaria 7(42.9%)
4. Enteric fever 1(0%)
5. ‘Viral’ synd. 4(25.0%)
Jindalet al CCM 2002

8. Risk Factors
•Diabetes mellitus
•Burns, wounds, multiple trauma
•Immunosuppressives
•Hepatic failure
•Invasive catheters, devices
•Hyposplenism
•Extremesofage
•Malignancy
•Organtransplant
•Radiationtherapy
•Renalfailure
•Indwellingurinecatheter
•A.I.D.S.

9. Pathophysiology
Infecting organism
Exotoxins
Stimulation & activation of macrophages, vascular endothelial and humoral
protein cascade system (both pro & anti inflammatory)
Endotoxins
Mediators (AAM, Complement, cytokines, ACTH,
histamine, NO, OFR, PAF, Kinins, etc.)
Activation of neutrophils & endothelial cells
OFRs, NO, Proteases, VAS (etc.)Cellular adhesion molecules (Selectins,
integrins, ICAM, etc.)
Tissue and organ injury

10. Organ Dysfunction
1.Cardiovascular
2.Pulmonary–ARDS
3.Neurological
4.Hepaticfailure
5.Renalfailure
6.Haematological:Coagulopathy
7.Others:Gastrointestinal,Metabolic

11. SIRS MODS
ARDS
ALI
Septicemia

13. Pathophysiologyof Pulmonary Damage
Acute microvascular damage
Hypoxic pulmonary
vasoconstriction
Increased permeability
•In situ thrombosis
•Platelet & neutrophil
aggregation
Increased Ppa
Increased RV load
Decreased RV function
Fluid exudation
Alveolar flooding
Hypoxic organ
damage
Hypoxaemia

14. •Cardiac output
•Depressed myocardium
•Cardiac failure
Cardiovascular Dysfunction
Sepsis
Mediators (NO)
Arteriolar and venous dilatation –damaged endothelium
Extravascular exudation
Hypotension
Normal to low filling
pressures
Decreased SVR
Septic shock

15. Diagnosis Issues in Sepsis
1.DiagnosisofInfection:Bacteraemia
•Centralvenouscatheterinfection
•Ventilatorassociatedpneumonia
•Surgicalsiteandintraabd.sepsis
•Acutecholecystitis;sinusitis
•Invasivecandidiasis
2.Organsystemdysfunction

16. Suspecting Sepsis
A.Clinicalsigns:
•Fever/hypothermia
•Unexplainedtachycardia,tachypnoea
•Signsofperipheralvasodilation
•Unexplainedshock,Obtundedmentality
B.HaemodynamicorLaboratoryparameters
•LowSVR/increasedC.O.
•IncreasedO
2consumption
•Leukocytosis/neutropaenia
•Thrombocytopaenia/DIC
•Unexplainedlacticacidosisoralterationsinliverorrenalfunction
•Increasedprocalcitonin,cytokines,CRP

17. Bacteraemia
Symptoms&Signs
•Fever,chills,hypothermia
•Leucocytosis,leftshiftofneutrophils,neutropaenia
•Hypoalbuminaemia;Renalfailure
Whattodo?
•Immediatebloodcultures(2to3)
•Skindecontamination
•Adequateblood(10-30mlperbottle)

18. CVCatheterInfection
•Bloodandcathremoval&culture
•Insertionsiteswab&culture
•Reinsertion–sameordifferentsite
Sinusitis
•SuspectedwithNTandNGtubes
•MaxillarysinusX-rays/CT
•Antralpuncture

19. Ventilator Associated Pneumonia
RiskFactors:
•Intubation,aspiration
•NG/enteralfeedingtube
•Useofantacids,PPIs
Whattodo?
•Bloodcultures
•Pl.aspiration(>10mm)
•Endotrachealsecretions
•Bronchoscopicspecimens

20. Management Issues
1.Useofantibiotics
2.Haemodynamicsupport
3.Sourcecontrol
4.Airwaysandlung
5.Immunologicaltherapy
6.Supportive&ancillarytherapies
7.Futureinterventions

21. Antibiotic use: Principles
1.Earlyuse;appropriatedrug
2.Avoidindiscriminatechoices
3.Carefullyanalysethecosts
4.Avoidglycopeptides(vancomycinorteicoplanin)forpresumed
Gram+veinfections(unlessMRSAsuspected)
5.Noroutineuseofantifungals
6.Empirictherapychosenonbasisofclinicalandprevalencedata

22. Antibiotic Use: Empiric choices
1.Severesepsis–noneutropaenia
•Carbapenammonotherapy
•3
rd
or4
th
generationcephalosporin
•Betalactamandaminoglycoside
2.Febrile,neutropaenia
•Extendedspectrumcarboxy-orureido-penicillinwithbeta
lactamaseinhibitor
3.DocumentedGram–vesepsis
•Aztreonammonotherapyorbetalactamandaminoglycoside

23. Haemodynamicsin Shock
Type PA occlusion
pressure
Cardiac
output
SVR
Cardiogenic ↑ ↓ ↑
Hypovolaemic ↓ ↓ ↑
Distributive (sepsis) ↓or N ↑or N or↓ ↓
Obstructive ↑or N or↓ ↓ ↑

24. HaemodynamicSupport: Goals
MAP >60-65mmHg
PCWP15-18mmHg
C.I.>4.0L/min/m
2
BSAforsepticorHmgicshock

25. HaemodynamicSupport
•Volumerepletion–CVPmonitoring
•OptimalHb(9-10gm/dl)
•Vasopressors:
Dopamine IncreasesCIandBP
Norepinephrine ImprovesBP,GFR
Dobutamine IncreasesCI(SV,HR)

26. Fluid Management in Shock
Fluid challenge (5-20 ml/kg over 10 min)
Assess haemodynamic response
(BP, HR, urine output, mental state)
CVP monitoring
Increase by >7 mm Hg
over initial value
Increase by <3 mm Hg
over initial value
Repeat fluid challengeDiscontinue
(Crystalloids are the mainstay of therapy)

27. Airway and Lungs -ARDS
•AdequatesupplementalO
2
•Endotrachealintubation–mechvent
•AvoidNIPPV
•Use‘permissivehypercapnia’–lowtidalvolume(P
plat<30cmH
2O)
•PronepositioningventilationifFiO
2requirement>0.60
•RestrictNOassalvagetherapy

28. Immunological Therapy: Do Not Use
•Corticosteroidsinhighdoses(30mg/kg)andforjust1-2days
•Ibuprofen
•Prostaglandins(esp.PGE
1)
•Pentoxifylline
•N-acetylcysteine
•Selenium
•AntithrombinIII
•Immunoglobulins
•GranulocyteColonyStimulatingFactor
•Growthhormones
•Haemofiltration(withrenalindication)

29. Ancillary Issues
1.DVTprophylaxis
2.Gastricmucosalcytoprotection
3.Nutritionalsupport
4.Bloodproducts
5.Intubationandmech.ventilation
6.Renalsupport-dialysis

30. Supportive Therapies
1.DVTprophylaxis:
-Lowdoseunfractionatedheparin(5000UBDorTDS)orLMWH
-Ifcontraindicated:mech.devices
2.Stress-ulcerprophylaxis
-Antacids,sucralfate
-H
2receptorantagonists
-Useofenteralnutrition

31. Nutritional Support
•Hypercatabolicstate
•Enteralnutritionpreferred
•Daily:Calories25-30Kcal/kgusualbodywt.
Proteins1.3–2g/kg
Glucose 30-70%ofnonproteincalories
Maintains.glucose<225mg/dl
Lipids 15-30%ofnonproteincalories

32. Risk Factors for Mortality in ARDS
RR (95% CI)
Sepsis 3.50(1.57-7.8)
>3 organ failure prior to admn. 3.00(1.43-6.3)
APACHE III >57 6.13(1.65-22.6)
SAPS II >39 10.18(1.49-69.7)
Gupta et al, Respirology2001

33. Reducing Sepsis Mortality:
New Directions
1.LowtidalvolumesinALI/ARDS
2.Earlygoal-directedtherapy(EGDT)
3.Useofdrotrecoginalpha(activated)
4.Moderatedosecorticosteroids
5.Tightcontrolofbloodsugar

34. Low Tidal Volumes in ALI
•TVof6ml/kgidealbodywt.significantlyreducesmortality
•Reducesvolutrauma
Questions: Acidosis
Distressingforpatient(sedation&staffeducation)
IntrinsicPEEP

35. Early Goal Directed Therapy
Anattempttoadjustcardiacpreload,afterloadandcontractilitytobalance
systemicO
2deliverywithO
2demand
•CVP,arterialline&Foleycath.
CVPof8-12mmHg;MAP>65mmHg;Urineoutputatleast0.5
ml/kg/h
•MonitoredforSVO
2>70%
Given:MoreIVfluids&bloodtransfusion
Moreinotropicsupport(dobutamine)

36. DrotrecoginAlfa (Activated)
•SeveredepletionofproteinCinsepsis–highmortality
•ActivatedproteinC:Anticoagulation
Profibrinolysis
Antiinflammatory
•Significantlyreducesmortality
•Windowperiod:48hrs
•Riskofbleeding
•Nobiochemicalmarkers
•Veryhighcost

37. Moderate-dose Corticosteroids
•Relativeadrenaldeficiencycommoninsepticshock
•Moderatedose(200-300mgHCdaily)forrefractorysepticshock
•BettertodoACTHtestbeforestartingsteroids

38. (Prigent et al 2003)
Cortisol >34 µg/dL Cortisol 34 µg/dL
Adrenal failure
No adrenal failureTissue resistance to
glucocorticoids
Replacement therapy
No teatment
Cortisol rise >9 µg/dL Cortisol rise <9 µg/dL
ACTH stimulation test
Cortisol >15 µg/dLCortisol 15 µg/dL
Plasma cortisol levels
Severe sepsis / septic shock
Corticosteroids in Sepsis

39. Tight Blood-Sugar Control
•Hyperglycaemia–common
•Hyperglycaemia(>100mg/dl,>6.1mmol/L)predisposestospecificICU
complications
•Highlevelsofinsulinlikegrowthfactorbindingproteinpredictsmortality
•Strictprotocoloflow-doseinsulinadmn.andrepeatedbloodsugar
assessments
•Especiallyforsurgicalpatients

40. Summary Recommendations
1.Formech.vent.,uselowTV
2.EGDT:Earlyaggressivetherapy:Generoususeoffluids&inotropes
3.Drotrecoginalphaforrecentonsetsepsis&septicshock
4.Moderate-doseCSforrefractoryshock
5.Tightcontrolofbloodsugarclosetophysiologicallevels

41. Agents in Development
Segara(afelimomab) AntiTNF-Fabantibodyfragment
CytoTAB AntiTNF-polyclonalantibody
Tifacogin Antitissuefactor
Pafase(PAF) DegradesPAF
Neurprex(Opebecan) Bactericidalpermeabilityincreasing
proteins
LipidAanalogs(antiendotoxins),AntiCD14monoclonalantibody,
dextran-boundpolymyxin,PhospholipaseIIinhibitors,NOscavengersand
NOSinhibitors(etc.)

42. SUMMARY
•Sepsiscontinuestothreatenhospitalservicesinvolvedincareofthe
sick
•Majorchangeshavetakenplaceinmostareas
•Intensivecareofferingan‘ICUpackage’hasimprovedsurvival