Adult ICU Sepsis

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Sepsis and Septic ShockOld Concepts, New Precepts

Babak Sarani, MDDivision of Traumatology and Surgical Critical

Care, Department of Surgery

University of Pennsylvania

Slide 3

Systemic Inflammatory Response Syndrome (SIRS)

Systemic inflammatory response to a variety of severe clinical insults. Manifested by two or more of the following:

Temperature >38C or 90 beats/min

Respiratory rate >20 breaths/min or PaCO2 12,000/mm3, 10% immature (band) forms

ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-1655.

Sepsis: ACCP/SCCM Definitions Sepsis

Systemic response to infection i.e., confirmed or suspected infection plus 2 SIRS criteria

Severe Sepsis

Sepsis associated with organ dysfunction, hypoperfusion, or hypotension

Septic Shock

Severe Sepsis that cannot be resuscitated or stabilized with IV fluids aloneACCP/SCCM Consensus Statement. Chest. 1992;101:1644.

Slide 5

Sepsis - ACCP/SCCM Definitions: The Update

Altered mental status

Edema or increased fluid balance

Hyperglycemia (absent diabetes)

Increased CRP or procalcitonin

Hypotension

Increased SvO2

CI >3.5 L/min/m2

Arterial hypoxemia (PaO2/FiO2 2 hours)

Increased serum Cr (>0.5 mg/dL)

Coagulopathy (INR >1.5)

Ileus (absent bowel sounds)

Thrombocytopenia (40 mg/dLor 70 mmol/L)

Hyperlactatemia (>1 mmol/L)

Decreased capillary refill or mottling

Levy MM et al. Crit Care Med. 2003.

Slide 6

Septic Shock : ACCP/SCCM Definition

Sepsis-induced hypotension (despite adequate fluid resuscitation with the presence of perfusion abnormalities) may include, but are not limited to:

lactic acidosis

oliguria

acute alteration of mental status

Patients receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.


Martin GS et al. NEJM 2003;348:1346

Population Adjusted Incidence of Sepsis (USA)

Slide 8

Comparative Incidence and Mortality

Angus DC et al. Crit Care Med. 2001; 29:1303

0

50

100

150

200

250

300

AIDS Breast CA Prostate CA 1st MI Sepsis

Incidence

Cas

esX1

,000

0

50000

100000

150000

200000

250000

AIDS BreastCA

ProstateCA

AMI Sepss

Mortality

Dea

ths\

year

Slide 9


Hospital Mortality Rate of Patients with Sepsis in the USA


Cases of Sepsis by Pathogen (USA)

Slide 11

Infection Source in Severe Sepsis

44.0%

17.3%9.1%

8.6%

6.6%

2.2%

8.0%

6.0%

10.8%RespiratoryBacteremiaGUAbdomenSoft tissueDeviceCNSEndocarditisOther


Slide 12Martin GS et al. NEJM 2003;348:1346

Characteristics of Patients with Sepsis

Organ Failure and Associated Mortality with Severe Sepsis

Organ Failure Occurrence, % Mortality, %

One 73.6 21.2

Two 20.7 44.3

Three 4.7 64.5

Four 1.0 76.2

Respiratory 45.8 40.1

Cardiovascular 24.4 32.4

Renal 22.0 38.2

Hematologic 20.6 22.8

Central nervous system 9.3 24.4

Hepatic 1.3 54.3


Slide 14

Determinants of Mortality Source control is most vital factor

Resuscitation/re-establish perfusion in 6 hrs

Appropriate antibiotic therapy within 1 hr of hypotension

Slide 15


Relationship of SIRS, Sepsis, and Infection

Van der Poll T, van Deventer SJH. Infect Dis Clin North Am.

Dynamic Nature of Sepsis

Slide 17

Hemodynamic Effects of Putative Septic Shock Mediators

Putative

Mediator

Arterial

Pressure

Cardiac

Output

Systemic

Vascular

Resistance

Ejection

Fraction

Miscellaneous

Effects

Endotoxin Decreased

(human, canine)

Increased

(human, canine)

Decreased

(human, canine)

Decreased

(human, canine)

WBC, pyrexia TNF, IL-1, IL-6

TNF Decreased(human, canine)

Increased

(human, canine)

Decreased

(human, canine)

Decreased

(canine)

Lactic acidosis,

pulmonary edema,

WBC, pyrexiaDIC, platelets

IL-1 Decreased(human, canine)

Increased

(human, canine)

Decreased

(human, canine)

Decreased

(canine)

Pyrexia,

platelets

IL-6No change

(canine)

No change

(canine)

No change

(canine)?

Hepatic acute phase

response

Kumar et al. J Cardiothorac Vasc Anesth. 2001.

Slide 18

Pathophysiology Distributive shock state

Vasodilation of arterioles low SVR, low BP nitric oxide (endothelium is the culprit!)

Compensate with tachycardia and elevated CO/CI

Pre-capillary A-V shunts Low BP bypass capillary resistance beds

Elevated SVO2 Elevated lactate

Metabolic Derangements in Sepsis

Elevated Lactate and MVO2:

Micro-anatomic shunts (non-nutrient capillaries)

Functional shunts (impaired microcirculatory vasomotor control)

Citric acid (Krebs) cycle defect with anaerobic glycolysis

Aerobic glycolysis with lactate production

Slide 20

Vasculature- Vasodilation- Vasoconstriction- Leukocyte Aggregation- Endothelial Cell Dysfunction

Cellular Dysfunction

Organs- Dysfunction- Metabolic Abnormalities

Myocardium- Depression- Dilatation

Shock

Refractory HypotensionMultiple Organ DysfunctionRecovery

Death

Nucleus

LysosomeMitochondria Actin/Myosin

Membranechannel

Membranereceptor

Pathogenesis of Septic Shock

Slide 21Waage A, Halstensen A, Espevick T. Lancet. 1987.

Serum Concentrations in Survivors and Nonsurvivorsof Septic Shock

150,000

TNF

units

/mL

seru

m

10

400600

1,0001,200

Serum from patientswho died

Serum from patientswho survived

Detection limitfor TNF

100,0001,400

1,000

200

Tumor Necrosis Factor (TNF)

Pathogen

Inflammation Coagulation

Monocyte

Tissue FactorCytokines

Pathophysiology of Sepsis

Slide 23

Coagulation CascadeSteps in

coagulationCoagulation

cascade

Initiation TF/VIIa

Propagation VIIIa

Thrombin activity

Fibrinogen Fibrin

IXa

IXX

Xa

IIVa

IIa

II indicates prothrombin; IIa, thrombin;IX, factor IX; IXa, activated factor IX; TF, tissue factor; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; X, factor X; Xa, activated factor X.

Weitz JI et al. Chest. 2001.

Slide 24

Coagulation in Sepsis

Bernard GR et al. N Engl J Med. 2001;344:699-709.

Inflammatory Responseto Infection

Thrombotic Responseto Infection

Fibrinolytic Responseto Infection

Endothelium

TAFI

PAI-1

Suppressedfibrinolysis

Neutrophil

Monocyte

IL-6IL-1TNF

Bacterial, viral, fungal or parasitic infection/endotoxin

Bacterial, viral, fungal or parasitic infection/endotoxin

IL-6

Tissue Factor

Tissue Factor

COAGULATION CASCADE

Factor Va

Factor VIIIa

THROMBIN

FibrinFibrin clot

Pathogenesis of Sepsis

Slide 26

Protein C Levels Decrease Before Diagnosis of Severe Sepsis

Mesters et al. Crit Care Med. 2000;28:2209-2216.

PC HEM

20

40

60

80

100

120

WBCFever

6 hr12 hr

18 hr24 hr

36 hr48 hr

60 hr72 hr

PC A

ntig

en (%

)

Severe Sepsis Patients

Septic Shock Patients

Average Time to Diagnose Severe Sepsis

Slide 27

Septic Shock The Spiral

Sepsis: Hemostatic Imbalance

Slide 29

GTP cGMP

BloodBlood EndotheliumEndothelium SmoothMuscle

SmoothMuscle

GTPGTP

cGMPcGMP

GC

L-ArgL-ArgO2O2

L-citrullineL-citrulline

GCGCNONO..

cNOSPlateletsPlatelets

Nitric Oxide in the Vasculature

Slide 30

GTP cGMP

BloodBlood EndotheliumEndothelium SmoothMuscle

SmoothMuscle

GTPGTP

cGMPcGMP

GC

L-ArgL-ArgO2O2

L-citrullineL-citrullineGCGC

NONO

iNOSPlateletsPlatelets

iNOS

cNOS

EndotoxinCytokinesEndotoxinCytokines

NONO

Nitric Oxide in Sepsis

Septic Shock Hemodynamics Warm (hyperdynamic) shock

hypotensive

tachycardia

tachypnea

bounding pulse

warm, well-perfusedextremities

skin flushed, moist

Cold (hypodynamic) shock

hypotensive

tachycardia

tachypnea

narrow, thready pulse

cold, poorly perfusedextremities

skin pale, dry

Slide 32

Dilemmas in Diagnosing the Septic Patient

Combine clinical exam and labs/imaging

Physical exam alone is NOT adequate

Elderly Cant mount a fever or leukocytosis

Ability to develop bandemia preserved

Immunosuppressed/steroids

Slide 33

Diagnosing Sepsis Lab tests: CBC, Chemistry, Cultures, lactate, SVO2

SVO2 is a measure of O2 extraction (NL 70%) UNDER-RESUSCITATED septic pts have a LOW SVO2 RESUSCITATED septic pts have a HIGH SVO2

Lactate is a measure of the severity of sepsis Lactate > 4 that does not correct in 6 hrs correlates with

mortality

Hemodynamics in sepsis Lactate

Weil & Afifi, Circulation 1970.

Slide 35

Septic Shock Hemodynamics CVP does not accurately estimate ventricular filling

pressures in the critically ill.

When PCWP (PAOP) is appropriately elevated with resuscitation, 90% of patients with septic shock exhibit a hyperdynamic circulatory state.

Hyperdynamic state persists to death.

Slide 36

Car

diac

Inde

x (L

/min

/m2)

Time (days)

Parker et al. Ann Intern Med. 1984

1

0

2

5

6

3

4

1 2 4 7 10 1 2 4 7 10

7

SurvivorsNonsurvivorsAll Patients

Cardiac Index in Septic Shock (post-1980)

Hypovolemia in Septic Shock Causes:

Venous pooling

Interstitial third-spacing

w Insensible losses (fever, RR) w Oral intake

Slide 38

Septic Shock Hemodynamics Hypodynamic septic shock in humans = inadequately

fluid-resuscitated septic shock

Slide 39Mizock BA. Crit Care Med. 1992;20:80-93.

Oxy

gen

Con

sum

ptio

n

Oxygen Delivery

Critical DeliveryThreshold

Lacti

c Acid

osis

Physiologic Oxygen SupplyPhysiologic oxygen supply dependency indicating a critical delivery threshold below which lactic acidosis ensues

Mizock BA. Crit Care Med. 1992;20:80-93.

Oxy

gen

Con

sum

ptio

n

Oxygen Delivery

Pathologic

Physiologic

Oxygen Delivery and Consumption

The relationship between oxygen delivery and consumption under physiologic and pathologic conditions is demonstrated on this chart.

Slide 41

Capillary

Vascular Abnormality

Arteriole

NeutrophilAggregation

VasoconstrictionVasodilation

Endothelial CellDestruction

Venule

Cell

Pathogenesis of Septic Shock

Slide 42

Treatment of Septic Shock Source Control When Possible

Based on Early Goal Directed Therapy

Broad, high dose, rapid administration of antibiotics

Consider Activated Protein C

Minimal role for steroidsSurviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2008. Critical Care Med

16% absolute reduction in mortality

Rivers, NEJM 2001; 345:1368

Cultures

Slide 44

Treatment - Fluids Endpoints of therapy

MAP > 65 mm Hg, HR < 100 bpm

UOP > 0.5 cc/kg/hr

SVO2 70% or more

CVP > 10-15 mm Hg Higher if known cardiomegaly or intubated

TTE showing cardiac filling

Until you no longer see improvement in hemodynamics following boluses

Slide 45

Failure to Intervene

Sebat CCM 2007; 35: 2568

Treatment - Steroids Recommended only for shock refractory to pressors *Multicenter, European, RCT

Pts with vasopressor-resistant hypotension Improved mortality if rise in cortisol following ACTH was < 9mcg/dL

and if baseline cortisol < 21 mcg/dL **CORTICUS larger, European, RCT

All pts with septic shock (regardless of vasopressor response) No difference in mortality but vasopressor sparing effect with

steroids ACTH stimulation could not predict who had endogenous cortisol

deficiency

*JAMA 2002; 288:862

**NEJM 2008; 358:111

Slide 47

Hemodynamics in sepsisDeterminants of oxygen delivery (DO2)

DO2

Cardiac output

Oxygen content

Heart rateStroke volume

Hemoglobin

PaO2

O2 Sat %

Slide 48

Failure to Intervene

Sebat CCM 35: 2568; 2007

Treatment

Slide 50

Treatment - Drotrecogin Alfa Protein C levels decrease before the onset of signs of

septic shock and are associated with worsened mortality

Activated protein C

Anticoagulant (inhibits Factors V and VIII) Stop microthrombi formation and prevent end-organ loss?

Endothelial cell stabilizer (anti-inflammatory) Stop excessive production of cytokines and apoptosis?

Slide 51

Treatment - Drotrecogin Alfa PROWESS RCT, 1690 pts, stopped early

532 surgical pts

6% decrease in mortality overall Greatest decrease if APACHE II score > 25

1.5% increase in risk of bleeding Equal between medical and surgical groups

Bernard. NEJM 2001; 344:699

Case StudyThe following are case studies that can be used for review of this presentation.

Review Cases

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Slide 53

Patient Presentation 45 year old male, fall down steps

No LOC

Arrives with c/o severe left hip/buttock pain

Slide 54

History PMH: None

PSH: None

Med: None

Allergy: None

Social: Occasional EtOH only

Travel: None

PE P 105 BP 110/55 RR 20 T 99.7

A&O with left hip/buttock pain, GCS = 15

Salient Findings:

Pelvis stable, intact grossly

Left buttock tensely swollen

LLE neurovascularly intact, no deformity

Perineal / Rectal exam normal

Slide 56

X-rays

Slide 57

X-rays

Scan

Slide 59

Labs WBC 19

Hg 11

Plt 171

Na 136; Cl 104; HCO3 12; BUN 42, Cr 4.2

Lactate 5.4 to 6.4

SVO2 39%

Slide 60

Hospital Course Pt talking on phone to wife regarding need for operation

Hospital Course Resuscitate, antibiotics

Co-oximeter catheter inserted, vasopressors

Endpoints: UOP, BP, CVP, lactate, SVO2 OR for serial debridements

Discharged to home with VAC dressings

Conclusion Tenets of Septic Shock and its Resuscitation

Source control is imperative

Broad spectrum, high dose, emperic antibiotics pending culture results

Resuscitate to established endpoints of perfusion and avoid excess fluid administration

Mixed venous oxygen saturation

Biochemical markers (lactate)

Echocardiogram to establish ideal CVP or L atrial pressure

Urine output

Mental StatusSlide 62

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Slide 65

References Martin GS, Mannino GM, Eaton S, et al. NEJM 2003;348:1546-54.

Angus DC, Linde-Zwirble WT, Lidicker J, et al. Crit Care Med 2001;29:1303-1310.

Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.

Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med. 2001;29:S28-S34.

Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin. 2000;16:251-287.

Levy MM, Fink MP, Marsahll JC, et al. Crit Care Med 2003;31:1250-1256

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Adult ICU Sepsis