What the best for EGDT: What the best for EGDT: ScvO2, Lactate or BE?

Sepsis: Defining a Disease Continuum

A clinical response arising from a nonspecific insult, including

Temperature oC or oC

HR Respirations 20/min WBC count 12,000/mm3 or4,000/mm3immature neutrophils

SIRS = Systemic InflammatoryResponse Syndrome

SIRS plus/with a presumed or confirmed infectious process

SepsisSepsisSIRSSIRSInfection/Infection/Trauma/shockTrauma/shock Severe SepsisSevere Sepsis

Adapted from: Bone RC, et al. Chest 1992;101:1644Opal SM, et al. 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/Trauma/shockTrauma/shock Severe SepsisSevere Sepsis

Sepsis with 1 sign of organ failureCardiovascular (refractory

hypotension)RenalRespiratoryHepaticHematologicCNSMetabolic acidosis

Septic Septic ShockShock

Initial Resuscitation

Diagnosis Antibiotic therapy Source Control Fluid therapy Vasopressors Inotropic Therapy Steroids Recombinant

Human Activated Protein C (rhAPC)[drotrecogin alfa(activated)]

Blood Product Administration Mechanical Ventilation Sedation, Analgesia, and

Neuromuscular Blockade in Sepsis

Glucose Control Renal Replacement Bicarbonate Therapy Deep Vein Thrombosis Prophylaxis Stress Ulcer Prophylaxis Limitation of Support

Index

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

49.2%

33.3%

0

10

20

30

40

50

60

Standard Therapyn=133

EGDTn=130

P = 0.01*

*Key difference was in sudden CV collapse, not MODS

28-day Mortality

Rivers E. N Engl J Med 2001;345:1368-77.

Early Goal-Directed Therapy Results

DEFINITION

SHOCK

The total body cellular metabolism is malfunctional, usually secondary to decreased delivery of oxygen to meet cellular needs and on occasions due to the inability of cells to utilize oxygen.

ShockClinical syndrome result from inadequate

tissue perfusion, often complicated by the cellular metabolic dysfunction

MODS (Multiple Organ Dysfunction Syndrome)MOFS (Multiple Organ Failure Syndrome)

Inadequate O2 delivery

Cellular injuryInflammatory mediators

DO2 = C.O x CaO2DO2 = C.O x Hb x Sa O2 +

dissolved O2

StrokeVolume

Preload

After load

Contractility Cardiac Output

Heart Rate

RhythmPassive complianceIntravasc. VolumeRelaxation

Aortic impedancePeriph. Vasc.Resist

Regional blood flow distribution in a 70kg healthy normal volunteer at rest

Organ

Kidney

Liver/GIT

Heart

Brain

Muscle

Skin

Organ size (kg)

0.3

1.5

0.3

1.4

2.5

30

Blood flow(l/min)

1.2

1.4

0.25

0.75

0.2

0.9

Blood flow(l/kg/min)

4.0

0.9

0.8

0.5

0.08

0.03

CO (%)

20 25

25 30

5

15

4

45

EGDT Inclusion criteria: two of SIRS criteria

SBP

EGDT for 6 hoursstandard th/ n = 133 EGDT th/ n = 130

CVP 8 12 mmHg, MAP 65 90mmHg, Urine 0.5cc/kg/hr, ScvO2 70%, SaO293%, Ht30%

BE ?Lactate ?

N Engl J M 2001; 345:1368 - 77

6 hrs after EGDTstandard vs EGDT

CVP increase MAP increase ScvO2 increase Lactate decrease Base deficit decrease pH increase APACHE II decrease SAP II decrease MODS

Hematocrit Prothrombin Time Partial thrombpl.Time Fibrinogen FDP D.Dimer Platelet count

N Engl J M 2001; 345:1368 - 77

Mortality and cause of in-hospital death

Standard Th/ EGDT PvalueVariable

In hospital mortality

All patient 59 (46.5) 38(30.5) 0.009Pts with severe sepsis 19 (30.0) 9 (14.9) 0.06Pts with septic shock 40 (56.8) 29 (42.3) 0.04Pts with sepsis syndrome 44(45.4) 35 (35.1) 0.07

no. (%)

28-day mortality 61(49.2) 40 (33.3) 0.0160-day mortality 70(56.9) 50(44.3) 0.03

Causes of in-hospital death

Sudden cardiovascular collaps 25/119 (21.0) 12/117 (10.3) 0.02Multiorgan failure 26/119 (21.8) 19/117(16.2) 0.27

N Engl J M 2001; 345:1368 - 77

Hemodynamicparameters-Preload (CVP, PCWP)-Afterload (MAP, SVR)-Contractility (SV)-Heart rate (BPM)-Shock index (HR/SBP)-Coronary perfusion pressure

DO2 parameter-PaO2-Hemoglobin-Cardiac output

Upstream endpoints of Resuscitation

GOAL- directed Therapy

MICROCIRCULATION

Down streammarkers of the effectiveness ofresuscitation

SvO2SvO2

LactateLactate

Base DeficitBase Deficit

(a (a v)CO2v)CO2

MediatorsMediators

PslCO2PslCO2

pHipHi

Number of publications on regarding microcirculation in humans

Schematic depiction of global circulation and microcirculatory blood flow in different organ systems with organ specific oxygen consumption and flow (VO & Q)1-3.

Systemic afterload could be interpreted as microvascularpreload, while systemic preload could be thought of as microvascular afterload.

Specific vasoactivemedication can be chosen to modulate microvascularperfusion.

SvO2DO2

PO2SaO2

ScvO2

SvO2(2)

SvO2(3)

SvO2(1)

-

SvO2

SvO2 SvO2 lowSvO2 low

ExerciseStressAnxiety

Hypoxemia

Heart failure

Hypovolemia

VO2 (N)VO2 (N)VO2 highVO2 high

CO lowCO lowCO highCO high

Increase O2ER

SaO2 lowSaO2 low SaO2 (N)SaO2 (N)

High PAOP /PE

High PAOP

Low PAOP

Anemia

Obstruction

CCM 2002; 30:2380-1

Carbohydrate metabolism

Acetyl CoA

Glucose

NAD+ NADH + H+

ATP ADP

Lactate

ATP ADP

Pyruvate

Phosphoenol-pyruvate2-Phosphoglycerate

3 Phosphoglycerate 1,3 Biphosphoglycerate

Glyceraldehyde 3-P

F 1,6PF-6PGlucose-6PATP ADP

ADP ATP

PDH

CO2 + H2O + 36 ATP

NADH NAD+

LDH

AnaerobicTCA cycle(Aerobic)

Lactate metabolism

Produced by: RBC, Skin, Brain, Skeletal muscle, Renal medulla, Intestinal mucosa, Other tissues

In general the level is less than 2mmol/L Daily production : 1500mmol/L Metabolized in the liver (60%) (Cori cycle)

in the cortex of kidney (30%) (neoglucogenesis)

The renal threshold excretion is 5 6 mmol/L

GlucoseGlucose

652 kcal673 kcal

(Gluconeogenesis)(Oxidation)

2 Lactate2 Lactate2 Pyruvate

(Oxidation)

Glucose

Alkalosis

AnoxiaEndotoxin

Thiamine Deficiency

+ 47 kcal

Lactate Shuttle

Causes of hyperlactatemia

Type A : Imbalance between O2 demand and Supply*Shock*Severe hypoxemia, CO poisoning*Severe anemia, excessive increase in O2 demand (seizure, hyperpyrexia, shivering, strenuous exercise)

Type B : Metabolic derangements

Causes of hyperlactatemia

Type B : Metabolic derangements* Cancer (tumor production or liver metastasis)* Liver failure* Cyanide poisoning* Alkalosis* Sepsis* Beta-2 agonist* Ketoacidosis* Vitamin deficiency: thiamine, biotine* Ethanol intoxication* Metformin* Inborn error of metabolism

Lactic acidosis Hyperlactatemia

A build up of lactic acid (lactatemia > 5 mmol/L) and metabolic acidosis (pH

Cori cycle(lactate glucose in the liver)

LIVER

MUSCLE

RBC

Beta-oxidation of FFA

2ATP

2ATP

2Lactate

6ATP 6ATP 6ADP6ADP

Blood lactate

Blood glucose

Glycogen

Glycolysis

2Lactate

Glucose

2Lactate2Lactate

GluconeogenesisGluconeogenesis

GlucoseGlucose

BLOOD

BE is the amount of base in millimolerequired to titrate 1 L of whole arterial blood to a pH of 7.40 with the sample fully saturated with oxygen at 37 C and a PaCO2 of 40mmHg

Mild : - 3 to 5 mmol/LModerate: - 6 to 14 mmol/LSevere: - 15 mmol/L

pH 6.10 + log HCO3-

PCO2 X 0.030=

BE caused by free water effect (BEfw)= 0.3 X (Na 140)

BE caused by changes in chloride (BEcl)= 102 - Clcor

Clcor = corrected chloride = Cl X 140/Na

BE caused by changes in albumin (BEalb)= 3.4 X (4.5 albumin)

BE net calculated from standard bicarbonate= BEfw + BEcl + BEalb + BEua

BE caused by unmeasured anions (BEua)= BE net (BEfw + BEcl +Bealb)

EVOLUTIVE STANDARD BASE EXCESS AND SERUM LACTATE LEVEL IN SEVERE SEPSIS AND SEPTICSHOCK PATIENTS RESUSCITATED WITH EARLY GOAL-DIRECTED THERAPY: STILL OUTCOMEMARKERS?

CLINICS 2006; 6 (1): 47 - 52

A retrospective study 65 cases Severe sepsis and septic shock Fluid resuscitation, inotropics, vasopressors ScvO2 70% SBE and lactate arterial blood Blood sample collected 6 hourly (first 24hr) ScvO2, lactate serum, SBE compared between

survivors and non-survivors during the first 5 days.

40 survivors and 25non-survivors

Characteristic All patients Survivor vs Nonsurvivor Pvalue

Age yrs Gender(female) (%) APACHE II * Days in ICU* ARDS no.(%) Mech.Ventilation no.(%) Dialysis no.(%) Septic Shock no.(%) Severe sepsis no.(%)

Sepsis sourcePneumonia no (%) Abdominal no (%) Urinary tract no (%) Soft tissue no(%) Catheter no (%) Unidentified no (%)

n=65 n=40 n=25

54 (33,69)28 (43)24(16,27)10(6,13)25(38)57(88)5(8)50(77)15(23)

41(27,61)20(50)21(12,25)10(6,13)16(40)32(80)2(5)28(70)12(30)

67(51,63)8(32)26(18,30)9(7,16)9(36)25(100)3(12)22(88)3(12)

40(62)10(16)5(8)4(6)3(4)3(4)

24(60)6(14)3(8)2(5)3(8)2(5)

16(64)4(16)2(8)2(8)0(0)1(4)

.99>.99.64.28

>.99

* Between groups there were difference in day 2, 3, 4 and 5

ScvO2

* Between groups there were difference in day 2, 3, 4 and 5

ScvO2

survivor

non survivor

# Within group showing differences between the days 3,4 5 vs day 1 amongthe survivor. * Between groups there was difference in day 5

SBE

* Between groups there was difference in day 2

Lactate

Evolutive SBE and serum lactate level are still considered to be outcome markers in septic patients treated with EGDT during their ICU stay.

Intensive Care Med (2001) 27 : 74 - 83

148 ICU cases (unselected)St Georges Hospital General ICU London

Prospective study BE and lactate level of arterial blood on admission and

and at 24h. Data in absolut numbers, medians with a range or

percentages 28 day mortality

mortality %n n

Medical causes 70 33 47Elective surgery 53 8 15Emergency surgery 25 10 40

17 pts passed away within 24 hrs

ROC for lactate

ROC for BE

AgeSex (M:F)BELactateSOFA on admissionSOFA at 24hrsAcute Renal F(%)Inotropes(%)MVent (%)Mortality(%)

68(21-91)37:26-8,1(-27.9-4.1)2.5(0.5- -4.1)5(0-14)6(0-16)22(34.9)11(17.4)44(69.8)36(57.1)

64(19-89)50:350.3 (-4-11.9)0.7(0.1-10.3)3(0-11)3(0-12)4(4.7)6(7.1)52(61.2)15(17.6)

*

****

*

*

Admission BE < - 4

Yes(n=63) No(n=85) *p

Admission lactate >1.5

Yes (n=57) No(n=91)

AgeSex(M:F)Base ExcessLactateSOFA on admissionSOFA at 24hrsAcute renal F(%)Inotropes(%)Mech.Ventilation (%)Mortality(%)

69(20-91)35:22-7.7(-27.9-11.7)2.9(1.6-15.4)4.5(0-14)5(0-16)9(15.7)20(35.1)41(71.9)35(61.4)

63(19-91)52:39-1.1(-14.8- 11.9)0.7(0.1-1.5)3(0-9)3(0-11)6(6.6)8(8.8)55(60.4)16(17.6)

******

*

*p< 0.05

24 lactate>1.0 24 lactate>1.0

Yes No Yes NoN at 24 hrs 27 21 16 67

Mortality(%) 22(81.5) 5(23.8)* 6(37.5) 8(11.9)*

Admission BE1.5Yes(n=81) No(n=67) *p

In patients whose BE decreased to greater than -2.5mmol/L and the lactate to less than 1.0mmol/l the mortality was less than 7%

If a patient on a general ward is able to demonstrate an improvement in these markers over the time, it takes to be assessed for admission to a higher level of care,admission is unnecessary as the prognosis will be good whatever the ultimate therapeutic strategy employed.

Crit Care Med 2004; 32:1637 - 1642

Early lactate clearance is associated with improved outcome in severe sepsis and septic shock

Prospective observational study Inclusion criteria; adult, ED, severe sepsis or septic

shock, a suspected sepsis source andA) two of four SIRS criteria and SBP 4mmol/L)

Exclusion criteria:

Lactate clearance was defined as the decrease in lactate from emergency department presentation to 6 hour

Lactate clearance

Lactate

LactateLactate

ED Presentation

ED Presentation

Hour 6___=

X 100

A positive value : a decrease or clearance of lactateA negative value : an increase in lactate after 6hrs of ED intervention

Septic Shock,%Platelet, permm3Prothrombin time, secsAlbumin, g/dLTotal bilirubin, mg/dLLactate, mmol/LLactate clearance,%

39.1224.000119.00014.7 3.03.0 0.71.3 2.26.1 4.438.1 34.6

70.2177,000 97,00019.2 8.32.6 0.73.0 4.18.0 4.712.0 51.6

.001

.03

Multivariate logistic regression modeling using statistically significant univariate variables associated with mortality

Septic shockPlateletProthrombin timeAlbuminTotal bilirubinLactateLactate clearance

2.473 (0.927 6.600)0.999 (0.994 1.004)1.140 (0.988 1.315)0.569 (0.267 1.212)1.045 (0.855 1.276)1.057 (0.945 1.182)0.989 (0.978 0.999)

.07

.69

.07

.14

.67

.34

.04

Variable OR(95% CI) p Value

p

Low lactate cl

Low lactate cl10% (n = 80) P Value

Therapy

P ValueLow lactate cl10% (n = 80)

Outcome

Outcome

In-hospital mortality rate, %30-day mortality rate, %60-day mortality rate, %

Severe sepsis, %Lactate, mmol/LIn-hospital mortality rate,%

Septic shock, %Lactate, mmol/LIn-hospital mortality rate,%

67.767.771.0

29.04.8 2.955.6

71.07.9 6.472.7

32.537.542.5

55.06.4 3.820.5

45.07.5 4.547.2

International Consensus Conference, Paris (27 28 April 2006): Hemodynamic monitoring in

shock and implications for management

International Consensus Conference, Paris (27 28 April 2006): Hemodynamic monitoring in shock and implications for management

Grading system of recommendationL1 (Level 1) : strong recommendationL2 (Level 2): weak recommendation

Quality of Evidence (QoE)High (grade-A)Moderate (grade-B)Low (grade-C)Very low (grade-D)

Question 1 : What are the epidemiologic and pathophysiologic features of shock in the ICU?

1. We recommend that shock be defined as a life threatening, generalized maldistribution of blood flow resulting in failure to deliver and/or utilize adequate amounts of oxygen, leading to tissue dysoxia ( L1 : B)

2. We recommend that hypotension (SBP

Question 1 : What are the epidemiologic and pathophysiologic features of shock in the ICU?

3. In the absence of hypotension, when shock is suggested by history and physical examination, we recommend that a marker of inadequate perfusion be measured (decrease ScvO2, SvO2, increase blood lactate, increase base deficit, perfusion-related low pH) (L 1: B)

4. Apart from lactate and base deficit, current evidence does not support the routine use of biomarkers for diagnosis or staging of shock.(L 1: A)

Question 1 : What are the epidemiologic and pathophysiologic features of shock in the ICU?

5. We recommend a target blood pressure during initial shock resuscitation of: For uncontrolled hemorrhage due to trauma: MAP of 40mmHg until bleeding is surgically controlled (L1 : B)For traumatic brain injury (TBI) without systemic hemorrhage: MAP of 90mmHg (L1 :C)For all other shock states : MAP>65mmHg.(L1 : B)

Question 4: What markers of the regional and microcirculation can be monitored and how

can cellular function can be assessed in shock?

1. We suggest serial measurements of lactates and/or base deficit as a predictor of outcome. (L2:B)

2. We do not recommend routine use of gastric tonometry, sublingual capnography, orthogonal polarization spectral (OPS) imaging and other techniques to assess regional or micro-circulation (L1:B)

Question 5 : What is the evidence for using hemodynamic monitoring to direct therapy in

shock?2. We do not recommend the routine use of the

pulmonary artery catheter for patients in shock (L1: A)

3. We recommend instituting goal-directed therapy without delay, in patients presenting with septic shock (within 6 h or ideally less), particularly where ScvO2 is below 70% (L1:B)

4. We do not recommend targeting supranormal oxygen delivery in patients with shock (L1:A)

Question 5 : What is the evidence for using hemodynamic monitoring to direct

therapy in shock?

5. a). We recommend frequent measurement of blood pressure and physical examination variables (including signs of hypoperfusion, urine output, and mental status) in patients with history and clinical findings suggestive of shock.b). We recommend invasive blood pressure measurement in refractory shock (L1 : D)

Summary EGDT should not be done late on ED/general ward. ScvO2 should be assessed carefully. The value is higher

than SvO2 (mixed venous) Evolutive BE and serum lactate level within five days can

be considered as outcome markers in severe sepsis and septic shock resuscitated with EGDT

BE higher than -2.5mmol/L and lactate less than 1mmol/L as cut off value of good ourcome.

BEua should be considered in critically ill setting. Early lactate clearance, more than 10% within 6 hrs ,can

be consider as a marker of outcome in severe sepsis and septic shock resuscitated with EGDT

Thank You

Patients demographic and clinical characteristics, by BE at admission and after 24h

BE at adm

ission < -4m

mol/L

BE at 24 h

Patients demographic and clinical characteristics, by lactate level at admission and after 24h

Lactate at admission >1.5 mmol/L mortality 61.4% 1.5 mmol/L 17.6%

Lactate at 24h > 1.0 mmol/L 81.5% 1.0mmol/L 23.8%