李建璋 MD, MScNEUH ED Staff Physician

Early Goal Directed Therapy for Early Goal Directed Therapy for Septic Shock in the Emergency Septic Shock in the Emergency Department of National Taiwan Department of National Taiwan University Hospital University Hospital

Preliminary ExperiencePreliminary Experience

Early Goal Directed Therapy for Early Goal Directed Therapy for Septic Shock in the Emergency Septic Shock in the Emergency Department of National Taiwan Department of National Taiwan University Hospital University Hospital

Preliminary ExperiencePreliminary Experience

The Continuum of Sepsis

Bone et al. Chest 1992;101:1644

SepsisSepsisSIRS Severe SepsisSevere Sepsis

Systemic Inflammatory Response Syndrome SIRS criteria

• Temp < 36° or > 38° C• HR > 90

• RR > 20 or PCO2 < 32

• WBC < 4k or > 12k or bands > 10%

Septic ShockSeptic Shock

The Continuum of Sepsis

Bone et al. Chest 1992;101:1644; Balk, RA

The Continuum of Sepsis

SepsisSepsisSIRSSIRS Severe Sepsis Septic ShockSeptic Shock

Sepsis plus Organ Dysfunction• Elevated Creatinine (>2)• Elevated INR (DIC)• Altered Mental Status (GCS <12)• Elevated Lactate (>4)• Hypotension that responds to fluid

Bone et al. Chest 1992;101:1644

The Continuum of Sepsis

SepsisSepsisSIRSSIRS Severe SepsisSevere Sepsis Septic Shock

Severe Sepsis and Hypotension• Hypotension that does NOT

respond to fluid (500cc bolus)

Bone et al. Chest 1992;101:1644

Why is this so Important?

• 750,000 cases/yr of severe sepsis in US

• 215,000 deaths/yr directly related to sepsis

• Tenth leading cause of death in USA• Rate of sepsis cases is increasing

faster than the population• 37% of severe sepsis patients come

through the ED

Why so Important? (cont’d)

Mortality of Severe Sepsis

0

50,000

100,000

150,000

200,000

250,000D

eath

s/Y

ear

AIDS* SevereSepsis‡

AMI†Breast Cancer§

†National Center for Health Statistics, 2001. §American Cancer Society,

2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001

Estimated Statistics in NTUH ED

• 2002 statistics– 1 year 994 episodes of bacteremia– Blood culture yield rate ~13%

• Estimation– 6626 blood culture drawn– Sepsis 50% 3313 Mortality (30day) 5%

165– Severe Sepsis 20% 1325 Mortality (30day) 22%

292– Septic Shock 5% 331 Mortality (30day) 50%

165

– 1 day 2.7 BSI 9 Sepsis 3.6 severe sepsis 0.9 septic shock 1.7 Mortality 0.85 early mortality

Major Advance in Sepsis Tx

• In the past 20 yrs, the mortality of severe sepsis/ septic shock remains dismal (40~50%)

• In the past 5 yrs, there were 4 major breakthroughs – Early goal directed therapy– Steroid for vasopressor resistant septic

shock– Activated protein C in septic shock– Intensive insulin for hyperglycemic pts

Early Goal-Directed Therapy (EGDT)

EGDT• Design

– Randomized, Blinded, Controlled trial• Patients

– 263 adults with severe sepsis and lactate > 4 or septic shock

• Intervention– 6 hours of algorithmic care which

optimized• CVP 8-12• MAP > 65• ScvO2 > 70%

• Outcome– Mortality in house, 28 day, and 60 day

Mixed venous O2

• ScvO2 correlates with SvO2 in shock states

Rivers, E. et al. N Engl J Med 2001;345:1368-1377

49.2%

33.3%

0

10

20

30

40

50

60

Standard Therapy n=133

EGDTn=130

P = 0.01*

28-day Mortality

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

EGDT Results

Early Interventions in Medicine

• AMI – “Time is Muscle”– ACC/AHA guidelines for STEMI

• Door-to-needle time for initiation of fibrinolytic therapy should be achieved within 30 minutes

• Door-to-balloon (or medical contact–to-balloon) time for PCI can be kept under 90 minutes.

• Stroke – “Time is Brain”– ASA

• IV rtPA is strongly recommended within 3 hours of onset of ischemic stroke (grade A).

• Trauma– Golden Hour – …the lives of severely injured peopl

e could be saved if treated by trauma specialists

Time Matters in the Treatment of Sepsis

Other Problem in Sepsis Management

• Inconsistency in early diagnosis

• Inadequate volume resuscitation

• Late or inappropriate antibiotics

• Failure to support depressed cardiac output

• Failure to control hyperglycemia

• Failure to treat adrenal insufficiency in refractory shock

Surviving Sepsis Campaign

• An international effort to increase awareness and improve outcome – reduce sepsis mortality by 25% in the next five years

• Experts representing 11 international organizations developed guidelines for management of severe sepsis and septic shock

• Includes early goal-directed therapy in addition to other measures

• Guidelines revealed at SCCM in Feb 2004– Critical Care Medicine March 2004 32(3):858-87.

Key Component • Early Goal Directed Therapy

– Fluid resuscitation – Use of vasopressors/inotropes– PRBC transfusions

• Early targeted antibiotics and source control

• Stress dose corticosteroid administration

• Recombinant human activated protein C (xigris) for severe sepsis

• Low tidal volume mechanical ventilation for ARDS

• Tight glucose control

Fluid

• Crystalloids and colloids are equally effective in restoring intravascular volume

SAFE study

• In a RCT conducted in 16 ICUs in Australia and New Zealand 6997 patients were randomized to receive either saline or 4% albumin for fluid resuscitation

The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256

Kaplan-Meier Estimates of the Probability of Survival

Primary Endpoint was 28 day mortality

What Pressors ? dopamine vs norepinephrine

• Several non-randomized studies and one small prospective randomized study for septic shock favored the use of norepinephrine

Norepinephrine vs Dopamine+/- Epinephrine in Septic Shock

Results of a prospective observational study

Claude, Critical Care Med 2000;28:2758

• Dobutamine – Used when cardiac output is inadequate,

as indicated by a reduced ScvO2

• Vasopressin – Considered in catecholamine refractory

hypotension – Increased adrenergic receptor sensitivity– Increases urine output in septic patients,

and increases creatinine clearance

A. Normal B. After one hour of hemorrhagic shock

VASOPRESSIN DEFICIENCY OCCURS IN SHOCK

Antibiotics and Source Control

Chest 1992;101:1644.Chest 2000;118(1):146

62%

28%

sepsis

Severesepsis

Septic shock

Effect of Inappropriate Antibiotics

Tight Glucose Control Improved Survival

Results of 250 DM Bacteremic Patients in NTIUH ED

Characteristics Total(n=250)

Survivor (n=220 )

Non-survivor (n=30)

P

HbA1c8.18+/-1.91 8.02+/-1.92 9.11+/-1.58 0.021*

microvascular complication 63 (30.4%) 77 (35.0%) 10 (33.3%) 0.857

macrovascular complication 99 (39.6%) 87 (39.5% ) 12 (40.0%) 0.962

Blood glucose 268.6+/-197. 7

263.0+/-195.8301.3+/-

209.30.342

Diabetic ketoacidosis 27 (10.8%) 19 (8.6%) 8 (26.7%) 0.007

HHS 25 (10.0%) 22 (10.0%) 3 (10.0%) 1.000

Adrenal Insufficiency in Septic Shock

• There is significant disagreement about how to best evaluate adrenal function in critical illness

• General agreement that a random cortisol of less than 25 is abnormal in this population

• Some screen with random cortisol and reserve ACTH stim test for those with low levels

• Use of total rather than free cortisol in those with hypoalbuminemia may overestimate the incidence of adrenal insufficiency

Steroids for Relative Adrenal Insufficiency

• Placebo-controlled,• randomized, double-blind study• 19 ICUs in France 300 patients• Infection + Temp >38.3 or <35.6C,

HR >90, SBP <90 or on vasopressor, UO < 0.5 mL/kg/hr or PaO2/FiO2 < 280,

• Lactate > 2 mmol/L, • mech ventilation

• Treatment• – Low doses compared to previou

s trials• Hydrocortisone 50 mg IV q 6 yrs• Fludrocortisone 50 mcg NGT qd• 7-day course• Laboratory• – Cosyntropin stimulation test• Relative adrenal insufficiency• Nonresponders = cortisol respons

e < 9 mcg/dLPrimary end point• – 28-day survival in nonresponder

s

Survival

Sepsis Bundle in NTUH ED

Since Jan 2006, We start EGDT in Selected Patients with Septic

Shock

Critical Area –Semi ICU

Blood Gas with Lactate Analysis Machine

Critical Area –SCVO2 Monitor

Pre-sep Catheter

Protocol

Special Sheet

Case Demonstration

• 57 male, underline DM• Conscious disturbance, fever• RR 32 PR 123 BT 38.7 BP 70/40 m

mHg• One touch: high• pH 7.1; HCO3- :12 • WBC 8900, Band 22%, CRP: 9• Hb 10.4• Lactate > 12

• CVP : 7 cm H2O

• SCVO2 : 49%

Initial Treatment

• Fluid: HAES 500 + NS 2000

• Vasopressor: Dopamine Levophed

• Abx: Augmentin (susp LRTI)

• Continuous insulin

2 hours later

• CVP 8 cm H2O• SBP 73 mmHg• Lactate > 12• Glucose 950

Treatment Adjustment

• Fluid: NS 4000• Vasopressor: Pitressin 3 amp in 500

cc NS run 24 hrs (0.04u/min)• Steroids: Dexamethasone 2mg IV• Increase continuous RI dose

4 hours

• BP 93/40 mmHg• Glucose 280• SCvO2 62• Lactate 5• CVP 11

• Keep fluid/ vasopressor/ insulin

6 hours

• BP 92/60 mmHg• Glucose 180• SCvO2 72• Lactate 1.8• CVP 13

• Goal achieved• Survive at 30 days

Preliminary Results in NTUH ED

• Period– 2006 Jan ~ 2006 Dec

• Setting – NTUH ED Critical Area – Staffed by Visiting Staff / Chief Resident/

Physician assistant– 9 Rooms with Monitor Devices– 1 SCVO2 monitor

• Patients– Randomly Selected patients with septic shock– Patients with severe sepsis not included in this

preliminary trial

Results

• A total of 30 patients with septic shock underwent EGDT in NTUH ED

• Mean age: 65.5 year old ( 37~90 y/o)• Male-female ratio: 9:2• In-hospital mortality: 9% (1/11)• Diagnosis: Urosepsis (3), Soft tissue

infection (3), Pneumonia (2), Biliary Tract Infection (1), Intra-abdominal infection (2)

A Case Control Study

• Case– A total of 30 patients underwent EGDT

• Control – Age/sex matched cases with traditional therapy– Time-matched density sampling method– 1:3 ratio

• Outcome– Primary: In-hospital Mortality– Secondary: Length of hospital stay

• Analysis:– Chi-square/Fisher exact/ Mann-Whitney U test– Kaplan-Meier survival analysis / Log-rank test

Characteristics between Case and Control Groups

Case (N=30)

Control (N=60)

P value

Age 65.45 +/- 20.6 64.72 +/- 21.5 0.97

Sex (male %) 18.2 % 18.2 % 1.0

Comorbidity

(Charlson Score)

2.54 +/- 1.9 3.21+/- 3.3 0.53

SBP 80.2 +/- 8.35 83.8 +/- 4.97 0.19

Acute Renal Failure

8/30 (26.7% ) 31/60 (51.6% ) 0.29

Acute Respiratory Distress

11 (36.4%) 18 (30.3%) 0.72

Conscious disturbance

5 (45.5%) 9 (27.3%) 0.28

30-day Mortality Rate

Primary Outcome

Log-Rank test: P=0.31

Days

EGDT group

Traditional group

Mortality: 30% vs. 45%

Survival Curve

Secondary Outcome

• Length of hospital stay ( alive )

– EGDT group: 17.1 +/- 15.9

– Traditional therapy: 26.2 +/- 12.9

(Non parametric test: P=0.159)

Results of Logistic Regression Analysis

Adjusted ORs

95% CI P value

Age 1.04 1.02~1.16 0.02

Charlson Score

1.2 1.01~2.14 0.04

EGDT 0.68 0.3~1.09 0.058

The Results Seems Promising !

The challenge is to make it work

• Despite the overwhelming benefit, institutions have been slow to adopt the protocol, as it requires – extra resources, time, effort, and

equipment.

Implement of EGDT

Key Points of Successful Delivery of Protocol in NTUH

• Leadership• Collaborative working group• A feasible sepsis protocol• Established Environment

– Critical Area, Semi ICU unit in ED• Equipment

– ScvO2 catheter covered by health insurance– ScvO2 Monitor– Lactate machine

• Knowledgeable Personnel– CR NSP

• Quality Assurance

Quality Assurance 6 hours

• 1. Lactate measured• 2. CVP / SCvO2 monitoring within 1 hours• 3. Culture obtained prior to abx• 4. Abx within 2 hrs• 5. CVP >12 cmH2O within 6 hrs• 6. SBP >90 or MAP >65 mmHg within 6 hrs• 7. SCvO2 (or SVO2) > 70% within 6 hrs• 8. Steroids on vasopressor• 9. Median glucose maintained <150

Outcome Measures

• Numerator:– Patients met with criteria of septic shock or

severe sepsis

• Outcome– In-Hospital Mortality– Length of hospital stay– Length of ICU stay– Length of ventilator-days

Conclusion

• EGDT is feasible in the NTU ED setting

• The effects of EGDT on outcome is promising

• We need more staff devoting to the practice of EGDT

• Critical care is a concept, not a location, which frequently begins with ED intervention and culminates in ICU admission and continued management

• Peter Safar

臨床醫師攻擊象徵敗血症的三頭獸臨床醫師攻擊象徵敗血症的三頭獸 HypoperfusionHypoperfusion, , HypotensionHypotension, , Organ dysfunctionOrgan dysfunction