From Guideline to Practice :Before and After Surviving Sepsis
Campaign in Taiwan
余忠仁臺大醫學院內科副教授
臺大醫院綜合內科部副主任
Surviving Sepsis Campaign
• Phase I: public awareness (2002)• Phase II: forming guidelines (2004)• Phase III: implementation of
guidelines• Goal: To reduce the mortality of
severe sepsis/septic shock by 25% within 5 years (2009)
Surviving Sepsis CampaignGuidelines for Management of Severe Sepsis and Septic Shock
Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873
Goal: To reduce the mortality of severe sepsis/septic shock by 25% in 2009
Management of Sepsis
• Infection control– Antibiotics, source control
• Hemodynamic support– Ventilation, infusion, pump
• Metabolic/endocrine support– Steroids, glucose control
• New drug– Activated protein C
49.2%
33.3%
0
10
20
30
40
50
60
Standard Therapy n=133
EGDTn=130
P = 0.01*
*Key difference was in sudden CV collapse, not MODS
28-day Mortality
Early Goal-Directed Therapy
River E. N Engl J Med 2001;345:1368.
Central venous arterial catheterization
CVP or FTc CVP < 8 mm Hg or FTc < 330 msec
CVP 8-12 mm Hg or FTc 330-360 msec
500-ml bolus of NS or LR every 30 min prn
< 65 mm HgMAP
MAP >65
Norepinephrine (adjustable dosage) ± vasopressin 0.04 U/min (fixed dosage)
Cl and ScvO2 or SvO2 Cl < 2.0 and ScvO2 or SvO2 <70%
Cl > 2.0 and ScvO2 or SvO2 >70%
Dobutamine 5 g/kg/min(adjustable dosage)
Goals achievedGoals achieved River E. N Engl J Med 2001;345:1368.
0
5
10
15
20
25
30
35
40
6 ml/kg
12 ml/kg
% M
ort
alit
y
ARDSnet Mechanical Ventilation Protocol
Results: Mortality
(The ARDS Network, NEJM 2000;342:1301)
61%53%
0%
20%
40%
60%
80%
100%
53%63%
0%
20%
40%
60%
80%
100%
Low-dose Steroids Placebo
Patients with Relative Adrenal Insufficiency (ACTH Test Non-
responders) (77%)
Patients Without Relative Adrenal Insufficiency (ACTH Test
Responders) (23%)
P=0.04 P=0.96
N=114 N=36 N=34N=115
28-d
ay M
ort
alit
yLow Dose Steroids and Septic Shock
(Annane et al. JAMA 2002;288:862)
• Relative adrenal insufficiency: max < 9 g/dL, 30-60 min after test
Intensive Glucose ControlInitial Infusion RateBlood Glucose Level (mg/dl) Insulin Infusion Rate(U/hr)110-220 2> 220 4
Blood Glucose Monitoring GuidelinesAccuchecks every hour during insulin infusion until four consecutive values are within 80-110 mg/dl, then every 4 hours. If tube feedings or total parenteral nutrition is held or discontinued, hold infusion and monitor blood glucose levels every 2 hours.
Insulin Infusion Titration GuidelinesBlood Glucose Level (mg/dl) Insulin Bolus and Infusion Rate41-60 Stop infusion61-80 Reduce rate by 0.1-0.5 U/hr81-111 No change unless decreased > 20% from previous result; if > 20%, decrease rate 20%111-120 Increase rate by 0.1-0.5 U/hr121-139 Increase rate by 0.5-1 U/hr> 140 Increase rate by 2 U/hr
The Role of IntensiveInsulin Therapy in the ICU
Berghe G, et al. N Engl J Med 2006;354:449-61
Su
rviv
al (
%)
100
00
Intensive treatment
Conventional treatment
Days after admission
20
40
60
80
100 200
P=0.02
300 400 500
MICU3 days
Su
rviv
al (
%)
100
00
Intensive treatment
Conventional treatment
Days after admission
80
84
88
92
96
50 100 150 200 250
P=0.01
Berghe G, et al. N Engl J Med 2001;345:1359-67
Surgical ICU
X
X
X
X
X
Coagulation Fibrinolysis Inflammation
Coagulationcascade
VIIIa
Va
Prothrombin
Thrombin
Tr Thrombomodulin
PC
PAI-1
aPC PS
Increased fibrinolysis
Neutrophiladhesion
Monocyteadhesion
CD1/MHC
Thrombin
Kaplan-Meier survival curves
Days from start of infusion to deathPROWESS. N Engl J Med 2001; 344:699-709
0 2814 217
80
70
90
100
0p = 0.006 (stratified log-rank test)
Sur
viva
l (%
)
placebo(n = 840)
Drotrecogin alfa (activated)(n = 850)
Kaplan-Meier survival curves
Days from start of infusion to death(NEJM 2001; 344:699, CCM 2005;33:2266)
0 2814 217
80
70
90
100
0
Sur
viva
l (%
)
Placebo (n = 840)
DrotAA (n = 850)
ENHANCE DrotAA (n = 2375)
PROWESS
Importance of Establishing Therapeutic Goals in Managing Sepsis
Therapeutic goals Absolute Mortality Rate
Low VT MV, Pplat 30 cmH2O 9%
Appropriate antibiotic within 4 hrs 24%
EGDT 16%
Decreasing lactate to 2 mmol/L in 24hrs 25%
Steroid when indicated 10%
Insulin for glucose 80-110 mg/dL 3% (12 ms)
DrotAA for APACHE II 25 13%
Compliance to Guidelines
• ED of Hospital general Universitario “Gregorio Maranon”, Spain– Determination of blood lactate 12.5%– Blood culture done: 85%– Antibiotic within 3 hrs: 32%– Aggressive fluid therapy: 46.6%– Vasoactive drugs when indicated: 43.3%– CVP monitor: 0%
(de Miguel-Yanes JM. Am J Emerg Med 2006;24:553)
The EGDT protocol utilized at Cooper University Hospital (an adaptation of the protocol by Rivers et al)
(Trzeciak S et al. Chest 2006;129:225)
Implementing EGDT in EDCooper University Hospital
• 22 cases treated with EGDT, 20 completed– Median time to reach each end point was 6
hours – EGDT used more fluids, PRBC requirement in
ED– EGDT reduced ICU PAC utilization
(Trzeciak S et al. Chest 2006;129:225)
Implementation of Sepsis Guideline
• Bundle approach–Surviving sepsis bundle
–STOP sepsis bundle
–Multiple Urgent Sepsis Therapies (MUST) protocol
Surviving Sepsis Bundles• Sepsis Resuscitation Bundle
(to be accomplished ASAP and scored over first 6 hrs)– Serum lactate– Blood culture prior to antibiotic– Broad-spectrum antibiotics administered within 3 hrs for ED admissions and
1 h for non-ED ICU admission– If hypotension (SBP<90, or MAP <70) and/or lactate > 4 mmol/L
• Deliver initial minimum of 20-40 ml/kg of crystalloid (or colloid equivalents)• Apply vasopressors for hypotension not responding to initial fluid resuscitation to
maintain MAP 65 mmHg
– If persistent hypotension despite fluid resuscitation or lactate > 4 mmol/L• Achieve CVP of 8 mmHg• Achieve ScvO2 of 70% or SvO2 of 65%
(2005 surviving Sepsis Campaign and the Institute for Healthcare Improvement)
Surviving Sepsis Bundles
• Sepsis Management Bundle(to be accomplished ASAP and scored over 24 hrs)– Low-dose steroids administered for septic shock in accor
dance with a standardized ICU policy– Drotrecogin alfa (activated) administered in accordance w
ith a standardized ICU policy– Glucose control maintained lower limit of normal, but < 15
0 mg/dL– Inspiratory plateau pressure maintained < 30 cmH2O for
MV patients
(2005 Surviving Sepsis Campaign and the Institute for Healthcare Improvement)
Sepsis Bundles:Compliance vs. non-compliance
(Gao F et al. Crit Care 2005;9:R764)
Compliance to 24 h sepsis bundle
Compliance (%)
Glucose control < 8.3mmol/L 64%
Low dose steroid 43%
Activated protein C 30%
Plateau pressure < 30cmH2O 85%
Total 30%
(Gao F et al. Crit Care 2005;9:R764)
STOP Sepsis BundleED patients First 3 months After 6 months
Achieve EGDT in 6 hrs 8% 26%
Lactate monitor at 6th hr 22% 52%
Appropriate steroid therapy 49% 67%
In 208 sepsis patients treated, all components of the bundle were completed in 24 patients, the mortality rate was 12.5%, compared with a 34.2% mortality rate in whom the protocol was not completed, (P = .008), and the hospital length of stay averaged 8.1 days compared with 11.9 days for the 184 patients in whom the bundle was not completed (P = .06).
Nguyen HB et al SCCM 34th Critical Care Congress: Abstract 44
(Nguyen HB et al. Crit Care Med 2007;35:1105)
STOP Sepsis Bundle• 2 years of intervention
Bundle completed (n=77)
Bundle not completed (n=253)
P value
CVP/ScvO2 by 2 hrs 100% 51.8% <0.01
Antibiotics by 4 hrs 100% 87.4% <0.01
CVP goal met at 6 hrs 100% 35.6% <0.01
SBP/MAP goal met at 6 hrs 100% 63.2% <0.01
ScvO2 goal met at 6 hrs 100% 22.9% <0.01
Appropriate steroids 77.9% 58.5% <0.01
Lactate clearance 79.2% 39.1% <0.01
(Nguyen HB et al. Crit Care Med 2007;35:1105)
STOP Sepsis Bundle
(Nguyen HB et al. Crit Care Med 2007;35:1105)
Before-after standardized hospital order set study
(Scott M et al. Crit Care Med 2006;34:2707)
(Scott M et al. Crit Care Med 2006;34: 2707)
Before-after standardized hospital order set study
Before (n=60) After (n=60) P value
28 day mortality
48.3% 30.0% 0.04
Hospital mortality
48.3% 35.0% 0.139
Hospital LOS (d)
12.19.2 8.97.2 0.038
(Scott M et al. Crit Care Med 2006;34:2707)
Multiple Urgent Sepsis
Therapies (MUST) Protocol
(Shapiro et al. Crit Care Med 2006;34:1025-32)
MUST Protocol• Nov, 2003- Jan, 2004, 116 protocol patients an
d Feb, 2000- Jan, 2001, 51 historical control– Mortality rate 20.3% vs 29.4% (p=0.3)– More fluid (4.0L vs. 2.5L, p<0.001)– Earlier antibiotics (90 vs. 120 mins, p<0.013)– More appropriate coverage (97% vs. 88%, p<0.05)– More vasopressor in the first 6 hrs (80% vs. 45%, p
<0.001)– Tighter glucose control (123 vs. 140, p<0.001)– Frequent assessment of adrenal function (82% vs.
10%, p<0.001)(Shapiro et al. Crit Care Med 2006;34:1025-32)
Economic implications of sepsis protocol
(Shorr AF et al. Crit Care Med 2007;35:1257)
Implementing Sepsis Guideline in Taiwan
• Education
• Practice module– “Bundled” approach– Quality improvement
indicator• Information technology
• Research
• Taiwan Guideline
EDGT Taiwan
• 資料來源:台大醫院急診部李建彰醫師
台大醫院急診部敗血症病患標準治療流程 懷疑感染
至少符合下列兩點1. 體溫高於 38.3 ℃ 或低於 36℃2. 心率大於 903. 呼吸速率大於 20 或 PaCO2 小於 324. 白血球大於 12k 小於 4k 或 band > 10%
重新評估
檢查 lactate 做兩套血液培養
區分敗血症嚴重程度
YesNo
敗血性休克定義:半小時內輸注 0.9NS 500 cc 依舊休克
嚴重敗血症超過一個以上器功能障礙 或 lactate 大於 4
敗血症給予適當廣效性抗生素住
進入早期目標導向治療 (early goal directed therapy)六小時內完成下列目標CVP 12-15 SBP 90-140 MAP 65-90 SvO2 >= 70
目標一: CVP 12-15 *未達目標 0.9NS 繼續全速輸注直到 CVP 8-12 然後維持 100cc/hr, 輸液超過 2000cc 0.9NS, 未達目標 , 考慮進入目標二CVP < 4 可考慮給予 HAES ( 肝硬化患者考慮給予 Albumin ), 使用正壓換氣或有腹壓上升情形 , 應維持 CVP >=15
目標二: SBP 90-140 MAP 65-90考慮給予昇壓劑 Dopamine, Norepinehrine 若一小時仍 SBP<90 考慮給予 Vasopressin (0.04u/min) 及 dexamethasone 2mg IV Q6h ( 如臨床懷疑 adrenal insufficiency 雖無敗血性休克亦應給予 )
目標三: SvO2 >= 70未達目標三 , 若 Hb<10 輸 PRBC, 若 Hb>10 給予 Dobutamine
Q2h 檢查 lactate 直到 lactate < 2
達成目標 ICU 住院
一小時內建立上腔中心靜脈導管一小時內給予適當廣效性抗生素視情形給予插管及機械換氣血糖以連續 insulin 控制在 90~150考慮給予 H2 blocker for stress ulcer prophylaxis
1. 本流程參考性治療準則 , 若病患合併有 UGI bleeding, CHF, ESRD 等狀況 應以臨床情況決定輸液治療的量及速度
2. 抽血間隔 : Lactate Q2h , DM 病患 sugar Q2H, 3. Cirrhosis 病患應檢查 albumin
Preliminary Results• Period
– 2006 Jan ~ 2006 May
• 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
Characteristics between Case and Control Groups
Case (N=11) Control (N=33) 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 3/11 (27.3% ) 17/33 (51.5% ) 0.29
Acute Respiratory Distress
4 (36.4%) 10 (30.3%) 0.72
Conscious disturbance 5 (45.5%) 9 (27.3%) 0.28
Primary Outcome
Log-Rank test: P=0.109
Days
EGDT group
Traditional group
Mortality: 9.1% vs. 45%
Survival Curve
Secondary Outcome
• Length of hospital stay ( alive )
– EGDT group: 20.1 +/- 25.9
– Traditional therapy: 27.4 +/- 22.9
(Non parametric test: P=0.22)
STOP Sepsis Bundle, Taiwan
資料來源:奇美醫學中心柳營院區加護醫學部侯清正主任
Pre-intervention period: yr 2005
Post-intervention period: yr 2006
過程面指標 Variable Pre-intervention
(N=46)Post-intervention
(N=66)P value
Lactate 執行地點的轉變 (%)
ER 7 68<0.001
ICU 67 29
On CVP 執行地點的轉變 (%)
ER 59 680.138
ICU 28 29
2 小時指標遵從率(%)
CVP 78 89 0.118
SVO2 50 82 <0.001
抗生素於 4 小時內給予 (%)
ER ICU
4672
6777
0.0330.515
6 小時指標遵從率(%)
CVP 8-12mmHgMAP >65mmHgSVO2 >70%3 項總達成率
70802622
79896450
0.2780.272
<0.0010.003
輸液及藥物的給予 輸液及藥物的給予 Variable Pre-intervention
(N=46)Post-intervention
(N=66)P-value
ER (cc) 841.3 ± 548.0 1657.8 ± 1481.1 <0.001
ICU (cc) 878.6 ± 700.5 1855.2 ± 1871.5 <0.001
Total (cc) 1719.9 ± 765.5 3513.0 ± 2349.2 <0.001
升壓劑ERICU
5798
6592
0.5180.369
Steroid (%) 62 69 0.51
Sugar (24 小時內 ) <150mg/dl
46 58 0.251
結果面指標 Variable(28-DAY)
Pre-intervention(N=46)
Post-intervention(N=66)
P value
呼吸器 free day 14.0±13.7 20.5±11.6 0.010
ICU free day 11.8±11.4 17.9±10.0 0.004
住院總 free day 7.5±9.2 11.8±8.9 0.013
死亡率 (%)severe sepsisseptic shockAll patients
503839
291620
0.5740.0310.032
住院總金額 186,568±227,561 107,565±84,736 0.029
敗血性休克 6 小時目標達成時間與其死亡率
P=0.005
9
26
42
0
20
40
60
6小時內達成 6小時後達成 都沒達成
%
Glycemic control protocol, KMUH• 資料來源:高雄醫學大學附設中和紀念醫院胸腔內科許超群醫師
Mortality and ICU LOS
¦~«×
87 88 89 90 91 92 93 94 95
¦Ê¤À¤ñ
0
10
20
30
40
50
Mortality RateICU LOS
Sugar Control Protocol, 三次大改版
ICU 專責主治醫師制
24-hours continuous feeding using an effective feeding protocol 是血糖能良好控制的重要基礎
轉出 ICU 前 , 改由 RI tid/sc 控制血糖 ,血糖值反而不穩定 .
有些病患在轉入 ICU 一段時間後血糖才開始高 , 故即使一開始的血糖值不高 ,所有的重症病患均應持續監控血糖 .
Infusion Insulin 之劑量變動極大 ,但血糖值均能在可接受範圍內
血糖值正常時仍需每日監控 ,每日一次
胰島素之使用隨血糖值調整 ,有時會斷斷續續使用
轉入 MICU 12 小時後 , 血糖獲得良好控制
24 h 後 , 血糖極少 > 200 mg/dL
Efficacy and Safety of Insulin Infusion Protocol
279 patients admitted to MICU during
Feb 1 to April 30, 2006
242 patients
222 patients
170 patients
116 patients54 patients
Readmission: 16 patientsMissing data: 19 patients
Oral feeding: 20 patients
ICU stay < 48 h: 52 patients
No insulin infusionduring ICU stay
With insulin infusionduring ICU stay
170 位病患轉入 MICU 時之血糖值分佈
116 位病患於 ICU 住院期間曾使用 insulin infusion therapy, 其中僅有 36.6% 於轉入 ICU 時即開始使用 insulin.
116 位病患於 ICU 住院期間曾使用 insulin infusion therapy, 其在 ICU 住院時 , 約六成的時間需使用 insulin.
ICU 住院 < 48 小時之病患僅有 28.8% 曾使用 insulin infusion therapy, ICU 住院 > 48 小時之病患則有 68.2% 曾使用 insulin infusion therapy,
Assessment of Adrenal function
NTUH Experiencecortisol 1
(<15) (n=16)cortisol 2
(15~34) (n=39)cortisol 3 (>34)
(n=19)P value
Cortisol (μg/dl) 8.583.69 22.025.81 62.0631.36
ACTH (pg/ml) 28.2532.94 39.6144.71 36.2924.39
28 days mortality No. (%)
2 (12.50%) 9 (23.08%) 12 (63.16%) 2vs3: 0.003
1vs3: 0.002
Inotropic agent n. Mean (SD)
1.06 (1.06) 0.85 (0.67) 1.42 (0.69) 2vs3: 0.003
Steroid supply No. (%)
13 (81.25%) 11 (28.21%) 7 (36.84%)
28 days mortality No. (%)
2 (15.38%) 5 (45.45%) 4 (57.14%)
NTUH experience
Responder Nonresponder (n=16) (n=9)
28 days mortality 3 (31.3%) 1 (11.1%)
Taper vasopressor 10 (62.5%) 7 (77.7%)
Use steroid 8 7
28 days mortality 3 (37.5%) 0 (0%)
Taper vasopressor 5 (62.5%) 6 (85.7%)
Not use steroid 8 2
28 days mortality 0 (0%) 1 (50%)
Taper vasopressor 5 (62.5%) 1 (50%)
NTUH, adrenal function assessment
• Septic shock, vasopresser >24 h, MICU
Jun~Sep, 2003(n=98)
Apr~Jun, 2005(n=119)
ACTH/Cortisol level
59 (60.2%) 78 (65.5%)
ACTH test 25 (25.5%) 20 (16.8%)
Use of rhAPC, Taiwan2005 2006 2007
Jan 6 4 11
Feb 6 7 9
Mar 4 15 10
Apr 6 16 5
May 4 15 13
Jun 10 6
Jul 6 8
Aug 7 7
Sep 5 5
Oct 5 2
Nov 7 6
Dec 5 7
Total 71 98 48
6.5% absolutereduction in
mortality
0
35
20
15
10
5
30
25
Mor
talit
y(%
)
Historical (n=63)
drotrecogin alfa(activated) (n=1
7)
30%
23.5%
NTUH historical control and EVBR study: 28-day all-cause mortality
• High risk of death • APACHE II score 25, or• Sepsis-induced multiple organ failure, or• Septic shock, or• Sepsis induced acute respiratory distress syndrome
• Treatment should begin as soon as possible once been identified
• No absolute contraindication • Weigh relative contraindications
Recombinant human Activated Protein C
Grade B
Dellinger, et. al. Crit Care Med 2004, 32: 858-873.
Industry and guideline
(Eichacker et al. N Engl J Med 2006;355:1640)
Risk vs, Benefits in the real world
(Eichacker & Natanson. Intensive Care Med 2007;33:396)
Implementing Sepsis Guideline in Taiwan
• Education
• Practice module– “Bundled” approach– Quality improvement
indicator• Information technology
• Research
• Taiwan Guideline
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