李建璋 MD, MSc NEUH ED Staff Physician Early Goal Directed Therapy for Septic Shock in the Emergency Department of National Taiwan University Hospital Preliminary Experience

The Continuum of Sepsis Bone et al. Chest 1992;101:1644 SIRS Systemic Inflammatory Response Syndrome SIRS criteria Temp 38° C HR > 90 RR > 20 or PCO 2 < 32 WBC 12k or bands > 10%

The Continuum of Sepsis Bone et al. Chest 1992;101:1644; Balk, RA

The Continuum of Sepsis Severe Sepsis 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 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 AIDS*Severe Sepsis ‡ AMI † Breast Cancer § † National Center for Health Statistics, § American Cancer Society, *American Heart Association ‡ 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 ScvO 2 > 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:

49.2% 33.3% Standard Therapy n=133 EGDT n=130 P = 0.01* 28-day Mortality Rivers E. N Engl J Med 2001;345: 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 people 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 (3):

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: 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 Severe sepsis Septic shock Effect of Inappropriate Antibiotics

Tight Glucose Control Improved Survival

Results of 250 DM Bacteremic Patients in NTIUH ED CharacteristicsTotal (n=250) Survivor (n=220 ) Non- survivor (n=30) P HbA1c 8.18+/ / / * 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 / / / 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 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 previous 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 response < 9 mcg/dL Primary end point – 28-day survival in nonresponders

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 –SCVO 2 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 mmHg One touch: high pH 7.1; HCO 3 - :12 WBC 8900, Band 22%, CRP: 9 Hb 10.4 Lactate > 12

CVP : 7 cm H 2 O

SCVO 2 : 49%

Initial Treatment Fluid: HAES NS 2000 Vasopressor: Dopamine  Levophed Abx: Augmentin (susp LRTI) Continuous insulin

2 hours later CVP 8 cm H 2 O 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 SCvO 2 62 Lactate 5 CVP 11 Keep fluid/ vasopressor/ insulin

6 hours BP 92/60 mmHg Glucose 180 SCvO 2 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 / / Sex (male %) 18.2 % 1.0 Comorbidity (Charlson Score) / / SBP / / 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: / –Traditional therapy: / (Non parametric test: P=0.159)

Results of Logistic Regression Analysis Adjusted ORs 95% CIP value Age ~ Charlson Score ~ EGDT ~

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 cmH 2 O within 6 hrs 6. SBP >90 or MAP >65 mmHg within 6 hrs 7. SCvO 2 (or SVO 2 ) > 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 Hypoperfusion, Hypotension, Organ dysfunction