A SYSTEMATIC REVIEW AND META-ANALYSIS OF EARLY GOAL-DIRECTED THERAPY FOR
SEPTIC SHOCK: THE ARISE, ProCESS AND ProMISe INVESTIGATORS
SUPPLEMENTARY MATERIALS
TABLE OF CONTENTS
PAGE
1. THE ARISE, PROCESS, PROMISE AND PRISM INVESTIGATORS
2
2. SEARCH STRATEGY
3
3. INCLUDED STUDIES
4
4. SUPPLEMENTARY FIGURES
5
Figure S1. Random-effects model for primary mortality outcome for patients presenting
to the emergency department with septic shock
Figure S2. In-hospital mortality
Figure S3. 28-day mortality
Figure S4. Receipt and duration of invasive mechanical ventilation
Figure S5. Receipt and duration of vasopressors
Figure S6. Receipt and duration of renal replacement therapy
Figure S7. Hospital length of stay
Figure S8. Effect of EGDT on primary mortality outcome for patients with septic shock
irrespective of presenting source
Figure S9. Funnel plot for primary mortality outcome of individual studies
5. SUPPLEMENTARY TABLES
17
Table S1. Receipt and duration of organ support
Table S2. ICU admission and length of stay in ICU and hospital
Table S3. Quality assessment for included studies
6. ACKNOWLEDGEMENTS
20
1
1. The ARISE, ProCESS, ProMISE and PRISM Investigators
ARISE Investigators: S.L. Peake, A. Delaney, M. Bailey, R. Bellomo, P.A. Cameron, D.J. Cooper,
A.M. Higgins, A. Holdgate, B.D. Howe, S.A.R. Webb, P. Williams; ProCESS Investigators: D.M. Yealy,
J.A. Kellum, D.T. Huang, P.C. Hou, A.E. Barnato, L.A. Weissfeld, F. Pike, T. Terndrup, H.E. Wang, F.
LoVecchio, M Filbin, N.I. Shapiro, D.C. Angus; ProMISe Investigators: D. Bell, J.F. Bion, T.J. Coats,
R.D. Grieve, D.A. Harrison, S.E. Harvey, R. Jahan, P.R. Mouncey, T.M. Osborn, G.S. Power, K.M.
Rowan, M.Z. Sadique, M. Singer, J. Tan, J.D. Young; PRISM Investigators: M.C. Reade.
Clinical Trials Unit, Intensive Care National Audit & Research Centre, London (J.Tan); Burns, trauma
and critical care research centre, University of Queensland, Brisbane, QLD and Joint Health Command,
Australian Defence Force, Canberra, ACT (M.C.Reade).
All other investigator affiliations and a full list of site investigators for the ARISE, ProCESS and ProMISE
trials are available in the original study reports:
ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R,
Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P (2014). Goaldirected resuscitation for patients with early septic shock. N Engl J Med 371:1496-506
ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F,
Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014). A randomised
trial of protocol-based care for early septic shock. N Engl J Med 370:1683-93
Mouncey PR, Osborn TM, Power, GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE,
Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015). Trial
of early, goal-directed resuscitation for septic shock. N Engl J Med, doi:10.1056/NEJMoa1500896
2
2. SEARCH STRATEGY
Medline via PUBMED interface
(central venous oxygen saturation) OR (goal directed therapy) OR (goal directed resuscitation) OR
(ScvO2) OR ScvO2) OR (clinical protocol) OR (sepsis protocol) OR (EGDT) OR (early goal directed
therapy)
AND
(sepsis) OR (septicaemia) OR (septic shock))
AND
(clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH
Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic
use[MeSH Subheading])
Searched from1/1/2000 until 15/1/2015
EMBASE and Cochrane Central Register of Clinical Trials via Ovid interface
1. exp *sepsis/
2. septicemia.mp.
3. exp Shock, septic/
4. 1 or 2 or 3
5. early goal directed therapy.mp.
6. EGDT.mp.
7. sepsis protocol.mp.
8. exp clinical protocols/
9. scvo2.mp.
10. goal directed resuscitation.mp.
11. goal directed therapy.mp.
12. 5 or 6 or 7 or 8 or 9 or 10 or 11
13. central venous oxygen saturation.mp.
14. 12 or 13
15. random:.tw.
16. clinical trial:.mp.
17. exp health care quality/
18. 15 or 16 or 17
19. 4 and 14 and 18
20. limit 19 to human
21. limit 20 to yr="2000-Current"
Searched from 1/1/2000 until 15/1/2015
3
3. INCLUDED STUDIES
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early
Goal-Directed Therapy Collaborative Group (2001). Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 8;345:1368-77
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock
Research Network (EMShockNet) Investigators (2010). Lactate clearance vs central venous oxygen
saturation as goals of early sepsis therapy: a randomised clinical trial. JAMA 303:739-46
ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup
T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014). A randomised trial of
protocol-based care for early septic shock. N Engl J Med 370:1683-93
ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R,
Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P (2014). Goaldirected resuscitation for patients with early septic shock. N Engl J Med 371:1496-506
Mouncey PR, Osborn TM, Power, GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE, Bell
D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015). Trial of
early, goal-directed resuscitation for septic shock. N Engl J Med, doi:10.1056/NEJMoa1500896
de Oliveira DS, Gottschald AF, Moura JD, Costa GA, Ventura AC, Fernandes JC, Vaz FA, Carcillo JA,
Rivers EP, Troster EJ (2008). ACCM/PALS haemodynamic support guidelines for paediatric septic
shock: an outcomes comparison with and without monitoring central venous oxygen saturation.
Intensive Care Med 34:1065-75
Wang X, Lu CJ, Gao FQ, Li XH, Yan WF, Ning FY (2006). Efficacy of goal-directed therapy in the
treatment of septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 18:661-4
Early Goal-Directed Therapy Collaborative Group of Zhejiang Province (2010). The effect of early goaldirected therapy on treatment of critical patients with severe sepsis/septic shock: a multi-centre,
prospective, randomised, controlled study. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22:331-4
Tian HH, Han SS, Lv CJ, Wang T, Li Z, Hao D, Shang QM, Wang XZ (2012). The effect of early goal
lactate clearance rate on the outcome of septic shock patients with severe pneumonia. Zhongguo Wei
Zhong Bing Ji Jiu Yi Xue 24:42-5
Yu B, Tian HY, Hu ZJ, Zhao C, Liu LX, Zhang Y, Zhu GJ, Wang LT, Wu XH, Li J (2013). Comparison
of the effect of fluid resuscitation as guided either by lactate clearance rate or by central venous oxygen
saturation in patients with sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 25:578-83
Lu N, Zheng R, Lin H, Shao J, Yu J (2014). Clinical studies of surviving sepsis bundles according to
PiCCO on septic shock patients. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 26:23-7
4
4. SUPPLEMENTARY FIGURES
Figure S1. Random-effects model of primary mortality outcome for patients presenting to the
emergency department with septic shock
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
38/130
59/133
13.06
Jones et al. (2010)
1.47 (0.82, 2.60)
34/150
25/150
11.09
ProCESS Investigators (2014)
1.17 (0.88, 1.55)
92/439
167/902
23.74
ARISE Investigators (2014)
0.98 (0.76, 1.26)
147/792
150/796
25.79
ProMISe Investigators (2015)
1.02 (0.80, 1.30)
184/623
181/620
26.32
Overall (I-squared = 56.7%, p = 0.055)
0.99 (0.79, 1.25)
495/2134
582/2601
100.00
NOTE: Weights are from random effects analysis
.3
1
Favours EGDT
3
Favours control
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another nonEGDT resuscitation strategy.
Random-effects model. The individual points denote the OR of each study and the lines either side the 95% confidence intervals.
The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard
therapy groups combined.
5
Figure S2. In-hospital mortality for patients presenting to the emergency department with septic
shock
A. Fixed-effect model
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
38/130
59/133
11.21
Jones et al. (2010)
1.47 (0.82, 2.60)
34/150
25/150
5.25
ProCESS Investigators (2014)
1.17 (0.88, 1.55)
92/439
167/902
23.47
ARISE Investigators (2014)
0.91 (0.69, 1.20)
115/793
125/797
28.95
ProMISe Investigators (2015)
1.05 (0.81, 1.36)
160/625
154/625
31.12
Overall (I-squared = 59.2%, p = 0.044)
1.00 (0.87, 1.16)
439/2137
530/2607
100.00
Events,
Events,
%
.3
1
Favours EGDT
3
Favours control
B. Random-effects model
Study
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
38/130
59/133
13.87
Jones et al. (2010)
1.47 (0.82, 2.60)
34/150
25/150
11.89
ProCESS Investigators (2014)
1.17 (0.88, 1.55)
92/439
167/902
24.01
ARISE Investigators (2014)
0.91 (0.69, 1.20)
115/793
125/797
24.57
ProMISe Investigators (2015)
1.05 (0.81, 1.36)
160/625
154/625
25.66
Overall (I-squared = 59.2%, p = 0.044)
0.98 (0.77, 1.25)
439/2137
530/2607
100.00
NOTE: Weights are from random effects analysis
.3
1
Favours EGDT
3
Favours control
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another nonEGDT resuscitation strategy. The individual points denote the OR of each study and the lines either side the 95% confidence
intervals. The vertical lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based
standard therapy groups combined.
6
Figure S3. 28-day mortality for patients presenting to the emergency department with septic
shock
A. Fixed-effect model
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.32, 0.87) 40/130
61/133
11.57
ProCESS Investigators (2014)
1.09 (0.83, 1.44) 103/405
197/827
26.76
ARISE Investigators (2014)
0.91 (0.70, 1.20) 117/792
127/797
29.90
ProMISe Investigators (2015)
1.02 (0.79, 1.32) 155/625
152/621
31.77
Overall (I-squared = 54.7%, p = 0.085)
0.95 (0.82, 1.10) 415/1952 537/2378 100.00
.3
Favours EGDT
1
Favours control
2
B. Random-effects model
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.32, 0.87) 40/130
61/133
14.31
ProCESS Investigators (2014)
1.09 (0.83, 1.44) 103/405
197/827
28.03
ARISE Investigators (2014)
0.91 (0.70, 1.20) 117/792
127/797
28.19
ProMISe Investigators (2015)
1.02 (0.79, 1.32) 155/625
152/621
29.47
Overall (I-squared = 54.7%, p = 0.085)
0.92 (0.73, 1.15) 415/1952 537/2378 100.00
NOTE: Weights are from random effects analysis
.3
Favours EGDT
1
Favours control
2
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another nonEGDT resuscitation strategy. The individual points denote the OR of each study and the lines either side the 95% confidence
intervals. The vertical lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based
standard therapy groups combined.
7
Figure S4. Receipt and duration of invasive mechanical ventilation for patients presenting to the
emergency department with septic shock
A. Receipt of invasive mechanical ventilation (fixed-effect model)
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
72/130
94/133
8.18
Jones et al. (2010)
0.85 (0.54, 1.34)
69/150
75/150
7.99
ProCESS Investigators (2014)
1.17 (0.92, 1.48)
165/434
307/892
24.59
ARISE Investigators (2014)
0.93 (0.76, 1.16)
238/793
251/798
34.57
ProMISe Investigators (2015)
1.02 (0.80, 1.31)
179/620
175/615
24.67
Overall (I-squared = 55.0%, p = 0.064)
0.97 (0.86, 1.10)
723/2127
902/2588
100.00
Events,
Events,
%
.3
1
Favours EGDT
2
Favours control
B. Receipt of invasive mechanical ventilation (random-effects model)
Study
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
72/130
94/133
10.99
Jones et al. (2010)
0.85 (0.54, 1.34)
69/150
75/150
12.89
ProCESS Investigators (2014)
1.17 (0.92, 1.48)
165/434
307/892
24.96
ARISE Investigators (2014)
0.93 (0.76, 1.16)
238/793
251/798
26.86
ProMISe Investigators (2015)
1.02 (0.80, 1.31)
179/620
175/615
24.31
Overall (I-squared = 55.0%, p = 0.064)
0.93 (0.77, 1.14)
723/2127
902/2588
100.00
NOTE: Weights are from random effects analysis
.3
1
Favours EGDT
2
Favours control
8
C. Duration of invasive mechanical ventilation (days) (fixed-effect model)
Study
N, mean
N, mean
%
(SD); EGDT
(SD); control Weight
ID
WMD (95% CI)
Rivers et al. (2001)
0.00 (-3.73, 3.73) 72, 9 (11.4)
ProCESS Investigators (2014)
-0.90 (-2.56, 0.76) 165, 6.4 (8.4) 307, 7.3 (9.4) 24.43
ARISE Investigators (2014)
1.50 (0.18, 2.82) 238, 6.2 (9)
ProMISe Investigators (2015)
0.40 (-1.04, 1.84) 179, 6.6 (7.1) 175, 6.2 (6.7) 32.48
Overall (I-squared = 40.2%, p = 0.171)
0.48 (-0.34, 1.30) 723
-4
Favours EGDT
0
Favours control
94, 9 (13.1)
4.81
251, 4.7 (5.4) 38.28
902
100.00
4
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval; WMD, weighted mean difference; SD,
standard deviation. The control was usual care or another non-EGDT resuscitation strategy.
The individual points denote the OR or WMD of each study and the lines either side the 95% confidence intervals. The vertical
lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy
groups combined.
9
Figure S5. Receipt and duration of vasopressors for patients presenting to the emergency
department with septic shock
A. Receipt of vasopressors (fixed-effect model)
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.56 (0.34, 0.92)
48/130
68/133
9.08
Jones et al. (2010)
1.29 (0.79, 2.10)
108/150
100/150
6.00
ProCESS Investigators (2014)
1.06 (0.84, 1.34)
269/439
540/902
29.32
ARISE Investigators (2014)
1.67 (1.34, 2.08)
605/793
525/798
26.57
ProMISe Investigators (2015)
1.25 (1.00, 1.57)
377/623
344/625
29.04
Overall (I-squared = 78.9%, p = 0.001)
1.25 (1.10, 1.41)
1407/2135
1577/2608
100.00
Events,
Events,
%
.3
1
Favours EGDT
3
Favours control
B. Receipt of vasopressors (random-effects model)
Study
ID
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.56 (0.34, 0.92)
48/130
68/133
15.10
Jones et al. (2010)
1.29 (0.79, 2.10)
108/150
100/150
15.10
ProCESS Investigators (2014)
1.06 (0.84, 1.34)
269/439
540/902
23.04
ARISE Investigators (2014)
1.67 (1.34, 2.08)
605/793
525/798
23.46
ProMISe Investigators (2015)
1.25 (1.00, 1.57)
377/623
344/625
23.30
Overall (I-squared = 78.9%, p = 0.001)
1.15 (0.86, 1.53)
1407/2135
1577/2608
100.00
NOTE: Weights are from random effects analysis
.3
1
Favours EGDT
3
Favours control
10
C. Duration of vasopressors (days) (fixed-effect model)
Study
N, mean
N, mean
%
ID
WMD (95% CI)
(SD); EGDT
(SD); control
Weight
Rivers et al. (2001)
-0.50 (-1.83, 0.83) 48, 1.9 (3.1)
68, 2.4 (4.2)
2.46
ProCESS Investigators (2014)
0.10 (-0.13, 0.33)
269, 2.6 (1.6)
540, 2.5 (1.6) 79.23
ARISE Investigators (2014)
0.10 (-0.39, 0.59)
605, 2.6 (4.9)
525, 2.5 (3.4) 18.31
Overall (I-squared = 0.0%, p = 0.682)
0.09 (-0.12, 0.29)
1407
1577
-2
Favours EGDT
0
Favours control
100.00
2
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval; WMD, weighted mean difference; SD,
standard deviation. The control was usual care or another non-EGDT resuscitation strategy.
The individual points denote the OR or WMD of each study and the lines either side the 95% confidence intervals. The vertical
lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy
groups combined.
11
Figure S6. Receipt and duration of renal replacement therapy for patients presenting to the
emergency department with septic shock
A. Receipt of renal replacement therapy
Study
Events,
Events,
%
ID
OR (95% CI)
EGDT
control
Weight
ProCESS Investigators (2014)
0.71 (0.36, 1.37)
12/382
35/796
11.88
ARISE Investigators (2014)
0.99 (0.74, 1.31)
106/793
108/798
50.39
ProMISe Investigators (2015)
1.09 (0.79, 1.51)
88/620
81/614
37.73
Overall (I-squared = 0.0%, p = 0.517)
0.99 (0.81, 1.22)
206/1795
224/2208
100.00
.3
Favours EGDT
1
Favours control
2
B. Duration of renal replacement therapy (days)
Study
N, mean
N, mean
%
Weight
ID
WMD (95% CI)
(SD); EGDT
(SD); control
ProCESS Investigators (2014)
-1.50 (-8.86, 5.86)
12, 7.1 (10.8)
35, 8.6 (12.4) 3.55
ARISE Investigators (2014)
-0.50 (-5.16, 4.16)
106, 8.5 (17.1)
108, 9 (17.7)
8.85
ProMISe Investigators (2015)
-0.30 (-1.78, 1.18)
88, 4.8 (5.5)
81, 5.1 (4.3)
87.60
Overall (I-squared = 0.0%, p = 0.950)
-0.36 (-1.75, 1.03)
206
224
100.00
-10
Favours EGDT
0
Favours control
10
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval; WMD, weighted mean difference; SD,
standard deviation. The control was usual care or another non-EGDT resuscitation strategy.
Fixed-effect model. The individual points denote the OR or WMD of each study and the lines either side the 95% confidence
intervals. The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based
standard therapy groups combined.
12
Figure S7. Hospital length of stay for patients presenting to the emergency department with
septic shock (days)
Study
N, mean
N, mean
%
ID
WMD (95% CI)
(SD); EGDT
(SD); control
Weight
Rivers et al. (2001)
0.20 (-3.12, 3.52)
130, 13.2 (13.8)
133, 13 (13.7)
7.38
Jones et al. (2010)
0.70 (-1.86, 3.26)
150, 12.1 (11.7)
150, 11.4 (10.9)
12.48
ProCESS Investigators (2014)
-0.70 (-1.90, 0.50)
439, 11.1 (10)
902, 11.8 (11.5)
56.68
ARISE Investigators (2014)
-1.00 (-3.66, 1.66)
793, 14.1 (17.3)
797, 15.1 (34.2)
11.50
ProMISe Investigators (2015)
1.10 (-1.51, 3.71)
625, 17.6 (23)
621, 16.5 (24)
11.96
Overall (I-squared = 0.0%, p = 0.650)
-0.28 (-1.18, 0.62)
2137
2603
100.00
-4
0
Favours EGDT
4
Favours control
EGDT denotes early goal-directed therapy; WMD, weighted mean difference; CI, confidence interval; SD, standard deviation.
The control was usual care or another non-EGDT resuscitation strategy
Fixed-effect model. The individual points denote the WMD of each study and the lines either side the 95% confidence intervals.
The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard
therapy groups combined.
13
Figure S8. Effect of EGDT on primary mortality outcome for patients with septic shock
irrespective of presenting source
A. Fixed-effect model by sub-group according to presenting source
Study
Events,
Events,
%
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
38/130
59/133
8.57
Jones et al. (2010)
1.47 (0.82, 2.60)
34/150
25/150
4.01
ProCESS Investigators (2014)
1.17 (0.88, 1.55)
92/439
167/902
17.95
ARISE Investigators (2014)
0.98 (0.76, 1.26)
147/792
150/796
25.30
ProMISe Investigators (2015)
1.02 (0.80, 1.30)
184/623
181/620
26.55
Subtotal (I-squared = 56.7%, p = 0.055)
1.01 (0.88, 1.16)
495/2134 582/2601 82.38
Wang et al. (2006)
0.48 (0.11, 2.11)
4/16
7/17
1.06
de Oliveira et al. (2008)
0.21 (0.07, 0.57)
6/51
20/51
3.66
EGDT Collaborative (2010)
0.46 (0.28, 0.74)
41/163
64/151
10.33
Tian et al. (2012)
3.55 (1.15, 10.99) 12/19
14/43
0.66
Yu et al. (2013)
1.56 (0.42, 5.78)
7/25
5/25
0.75
Lu et al. (2014)
1.06 (0.34, 3.35)
7/40
7/42
1.17
Subtotal (I-squared = 72.2%, p = 0.003)
0.61 (0.43, 0.86)
77/314
117/329
17.62
0.94 (0.82, 1.07)
572/2448 699/2930 100.00
ID
Source: ED
.
Source: other/unclear
.
Overall (I-squared = 70.7%, p = 0.000)
.1
1
Favours EGDT
10
Favours control
14
B. Random-effects model by sub-group according to presenting source
Study
Events,
Events,
%
OR (95% CI)
EGDT
control
Weight
Rivers et al. (2001)
0.52 (0.31, 0.86)
38/130
59/133
11.20
Jones et al. (2010)
1.47 (0.82, 2.60)
34/150
25/150
10.26
ProCESS Investigators (2014)
1.17 (0.88, 1.55)
92/439
167/902
14.59
ARISE Investigators (2014)
0.98 (0.76, 1.26)
147/792
150/796
15.03
ProMISe Investigators (2015)
1.02 (0.80, 1.30)
184/623
181/620
15.14
Subtotal (I-squared = 56.7%, p = 0.055)
0.99 (0.79, 1.25)
495/2134 582/2601 66.22
Wang et al. (2006)
0.48 (0.11, 2.11)
4/16
7/17
3.17
de Oliveira et al. (2008)
0.21 (0.07, 0.57)
6/51
20/51
5.56
EGDT Collaborative (2010)
0.46 (0.28, 0.74)
41/163
64/151
11.66
Tian et al. (2012)
3.55 (1.15, 10.99) 12/19
14/43
4.83
Yu et al. (2013)
1.56 (0.42, 5.78)
7/25
5/25
3.86
Lu et al. (2014)
1.06 (0.34, 3.35)
7/40
7/42
4.70
Subtotal (I-squared = 72.2%, p = 0.003)
0.77 (0.35, 1.68)
77/314
117/329
33.78
0.87 (0.65, 1.17)
572/2448 699/2930 100.00
ID
Source: ED
.
Source: other/unclear
.
Overall (I-squared = 70.7%, p = 0.000)
NOTE: Weights are from random effects analysis
.1
1
Favours EGDT
10
Favours control
EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another nonEGDT resuscitation strategy. The individual points denote the OR of each study and the lines either side the 95% confidence
intervals. The vertical lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based
standard therapy groups combined.
Post-hoc analysis of the interaction between presenting source (emergency department versus general ward/ intensive care unit
or source unknown) and the effect of EGDT did not find any sub-group interaction (P=0.51)
15
SE of log(OR)
Figure S9. Funnel plot for primary mortality outcome of individual studies
Primary
Secondary
0.0
0.2
0.4
0.6
0.8
0.2
0.5
1.0
Odds ratio
2.0
5.0
The dots represent those studies conducted in patients presenting to the emergency department with septic shock (primary
objective) and the triangles those studies in which some or all the patients enrolled were from the general ward and /or
intensive care unit or the source was unable to be determined from either the published article or from direct communication
with the author (secondary objective).
16
5. SUPPLEMENTARY TABLES
Table S1. Receipt and duration of organ support
Author
Invasive
Duration of
Vasopressor
Duration of
ventilation, %
ventilation, days
support, %
vasopressors, days
EGDT
Control
EGDT
Control
EGDT
Control
RRT, %
Duration of
RRT, days
EGDT
Control
EGDT
Control
EGDT
Control
Primary objective
Rivers et al.
55.4
70.7
9.0 ± 11.4
9.0 ± 13.1
36.1
51.1
1.9 ± 3.1
2.4 ± 4.2
NA
NA
NA
NA
Jones et al.
46.0
50.0
NAa
NAa
72.0
66.7
NA
NA
NA
NA
NA
NA
ProCESS Investigators
38.0
34.4
6.4 ± 8.4
8.4 ± 7.3
61.3
59.9
2.6 ± 1.6
2.5 ±1.6
3.1
4.4
7.1 ± 10.8
8.6 ± 12.4
ARISE Investigators
30.1
31.5
6.2 ± 9.0
4.7 ± 5.4
76.6
65.8
2.6 ± 4.9
2.5 ± 3.4
13.4
13.6
8.5 ± 17.1
9.0 ± 16.9
ProMISe Investigators
28.9
28.5
6.6 ± 7.1
6.2 ± 6.7
60.5
55.0
NA
NA
14.2
13.2
4.8 ± 5.5
5.1 ± 4.3
Secondary objective
Wang et al.
68.8
76.5
NA
NA
100
100
NA
NA
18.8
29.4
NA
NA
De Oliviera et al.
70.6
80.4
NAb
NAb
72.6
74.5
NAb
NAb
NA
NA
NA
NA
EGDT collaborative
NA
NA
13.2 ± 1.5
14.4 ± 1.6
NA
NA
NA
NA
NA
NA
NA
NA
Tian et al.
NA
NA
6.4 ± 4.0
5.7 ± 4.2c
NA
NA
NA
NA
NA
NA
NA
NA
Yu et al.
76.0
80
NA
NA
64.0
64
NA
NA
NA
NA
NA
NA
Lu et al.
100
100
6.0 ± 1.2
4.1± 0.9
100
100
NA
NA
NA
NA
NA
NA
Data presented as mean ± SD or proportions (%) unless otherwise indicated. ProCESS denotes Protocolized Care for Early Septic Shock; ARISE, Australasian Resuscitation in Sepsis Evaluation;
ProMISe, Protocolised Management in Sepsis; EGDT, early goal-directed therapy; NA, not available; RRT, renal replacement therapy. The primary objective included only those studies in which
patients presented to the emergency department with septic shock. The secondary objective included those studies in which the presenting source was the emergency department and the ward or
intensive care unit or where the source was not known. The control for all analyses was usual care or another non-EGDT resuscitation strategy. For ProCESS, data presented for the control group is
usual care and protocol-based standard therapy groups combined.
a
Ventilator-free days for the EGDT and control groups 9.9 ± 11.1 and 11.1 ± 9.3, respectively.
b
For the EGDT and control groups, median (interquartile range) duration of ventilation 3 (0-7) and 4 (1-13) days and duration of vasopressor support 3 (2-5) and 3 (14-67) days, respectively.
c
Data presented for 10% lactate clearance group only. For the 30% lactate clearance group, duration of ventilation 4.0 ± 3.1 days.
17
Table S2. ICU admission and length of stay in ICU and hospital
Author
ICU admission
ICU length of stay
Hospital length of stay
%
days
days
EGDT
Control
EGDT
Control
EGDT
Control
Primary objective
Rivers et al.
NA
NA
NA
NA
13.2 ± 13.8
13 ± 13.7
Jones et al.
100
100
5.6 ± 7.4
5.9 ± 8.5
12.1 ± 11.7
11.4 ± 10.9
ProCESS Investigators
91.3
85.8
5.1 ± 6.3
4.9 6.5
11.1 ± 10.0
11.8 ± 11.5
ARISE Investigators
91.5
83.0
4.9 ± 7.2
4.8 ± 5.9
14.1 ± 17.3
15.1 ± 34.2
ProMISe Investigators
88.2
74.6
5.7 ± 8.1
6.4 ± 9.8
17.6 ± 23.0
16.5 ± 24.0
Secondary objective
Wang et al.
100
100
NA
NA
NA
NA
De Oliviera et al.
100
100
7 (5-18)
9 (5-17)
NA
NA
EGDT collaborative
100
100
19.9 2.7
20.6 1.9
NA
NA
Tian et al.a
100
100
11.3 ± 6.0
7.9 ± 6.0a
NA
NA
Yu et al.
100
100
10.0 ± 4.0
8.0 ± 3.0
35 ± 16
29 ± 11
Lu et al.
100
100
9.5 ± 2.5
7.1 ± 3.1
NA
NA
Data presented as mean ± SD or proportions (%) unless otherwise indicated. ProCESS denotes Protocolized Care for Early
Septic Shock; ARISE, Australasian Resuscitation in Sepsis Evaluation; ProMISe, Protocolised Management in Sepsis; EGDT,
early goal-directed therapy; NA, not available. The primary objective included only those studies in which patients presented to
the emergency department with septic shock. The secondary objective included those studies in which the presenting source
was the emergency department and the ward or intensive care unit or where the source was not known. The control for all
analyses was usual care or another non-EGDT resuscitation strategy. For ProCESS, data presented for the control group is usual
care and protocol-based standard therapy groups combined.
a
Data presented for 10% lactate clearance group only. ICU length of stay for 30% lactate clearance group 7.5 ± 4.0 days.
18
Table S3. Quality assessment for included studiesa
Author
Random
sequence
generation
Allocation
concealment
Blinding of
participants and
personnel
Blinding of
outcome
assessment
Incomplete
outcome data
Selective
reporting
Other sources
of bias
Primary objective
Rivers et al.
Low
Low
High
Low
Low
Unclear
Low
Jones et al.
Low
Low
High
Low
Low
Unclear
Low
ProCESS Investigators
Low
Low
High
Low
Low
Low
High
ARISE Investigators
Low
Low
High
Low
Low
Low
Low
ProMISe Investigators
Low
Low
High
Low
Low
Low
Low
Secondary objective
Wang et al.
Unclear
Unclear
High
Unclear
Low
Unclear
Unclear
De Oliviera et al.
Low
Low
High
Low
Low
Low
High
EGDT collaborative
Low
Unclear
High
Unclear
Low
Unclear
Unclear
Tian et al.
Low
Unclear
High
Unclear
High
Unclear
Unclear
Yu et al.
Low
Unclear
High
Unclear
Low
Unclear
Unclear
Lu et al.
Low
Unclear
High
Unclear
Low
Unclear
Unclear
ProCESS denotes Protocolized Care for Early Septic Shock; ARISE, Australasian Resuscitation IN Sepsis Evaluation; ProMISe, Protocolised management In Sepsis; EGDT, early goal-directed
therapy. The primary objective included only those studies in which patients presented to the emergency department with septic shock. The secondary objective included those studies in which the
presenting source was the emergency department and the ward or intensive care unit or where the source was not known.
a
Quality assessment conducted independently by two assessors not involved in the design, conduct, analysis and reporting of the included studies (ADa, TI).
19
6. ACKNOWLEDGEMENTS
We are grateful to Ms Sue Rockliff (Librarian, The Queen Elizabeth Hospital, Adelaide, South Australia)
for assistance with the literature search.
20