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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). Goal-

directed 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 interface1. 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). Goal-

directed 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

goal-directed 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

NOTE: Weights are from random effects analysis

Overall (I-squared = 56.7%, p = 0.055)

Jones et al. (2010)

ProMISe Investigators (2015)

Rivers et al. (2001)

ProCESS Investigators (2014)

Study

ID

ARISE Investigators (2014)

0.99 (0.79, 1.25)

1.47 (0.82, 2.60)

1.02 (0.80, 1.30)

0.52 (0.31, 0.86)

1.17 (0.88, 1.55)

OR (95% CI)

0.98 (0.76, 1.26)

495/2134

34/150

184/623

38/130

92/439

Events,

EGDT

147/792

582/2601

25/150

181/620

59/133

167/902

Events,

control

150/796

100.00

11.09

26.32

13.06

23.74

%

Weight

25.79

0.99 (0.79, 1.25)

1.47 (0.82, 2.60)

1.02 (0.80, 1.30)

0.52 (0.31, 0.86)

1.17 (0.88, 1.55)

OR (95% CI)

0.98 (0.76, 1.26)

495/2134

34/150

184/623

38/130

92/439

Events,

EGDT

147/792

Favours EGDT Favours control 1.3 1 3

EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another non-

EGDT 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


ID

Jones et al. (2010)


1.00 (0.87, 1.16)

0.91 (0.69, 1.20)

0.52 (0.31, 0.86)

1.05 (0.81, 1.36)

OR (95% CI)

1.47 (0.82, 2.60)

1.17 (0.88, 1.55)

439/2137

115/793

38/130

Events,

160/625

EGDT

34/150

92/439

530/2607

125/797

59/133

Events,

154/625

control

25/150

167/902

100.00

28.95

11.21

%

31.12

Weight

5.25

23.47

1.00 (0.87, 1.16)

0.91 (0.69, 1.20)

0.52 (0.31, 0.86)

1.05 (0.81, 1.36)

OR (95% CI)

1.47 (0.82, 2.60)

1.17 (0.88, 1.55)

439/2137

115/793

38/130

Events,

160/625

EGDT

34/150

92/439


B. Random-effects model




Study




Jones et al. (2010)

ID

0.98 (0.77, 1.25)

1.05 (0.81, 1.36)

0.52 (0.31, 0.86)

1.17 (0.88, 1.55)

0.91 (0.69, 1.20)

1.47 (0.82, 2.60)

OR (95% CI)

439/2137

160/625

Events,

38/130

92/439

115/793

34/150

EGDT

530/2607

154/625

Events,

59/133

167/902

125/797

25/150

control

100.00

25.66

%

13.87

24.01

24.57

11.89

Weight

0.98 (0.77, 1.25)

1.05 (0.81, 1.36)

0.52 (0.31, 0.86)

1.17 (0.88, 1.55)

0.91 (0.69, 1.20)

1.47 (0.82, 2.60)

OR (95% CI)

439/2137

160/625

Events,

38/130

92/439

115/793

34/150

EGDT



EGDT 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


6

Figure S3. 28-day mortality for patients presenting to the emergency department with septic

shock

A. Fixed-effect model




ID

Study



0.95 (0.82, 1.10)

1.09 (0.83, 1.44)

0.91 (0.70, 1.20)

OR (95% CI)

1.02 (0.79, 1.32)

0.52 (0.32, 0.87)

415/1952

103/405

117/792

EGDT

Events,

155/625

40/130

537/2378

197/827

127/797

control

Events,

152/621

61/133

100.00

26.76

29.90

Weight

%

31.77

11.57

0.95 (0.82, 1.10)

1.09 (0.83, 1.44)

0.91 (0.70, 1.20)

OR (95% CI)

1.02 (0.79, 1.32)

0.52 (0.32, 0.87)

415/1952

103/405

117/792

EGDT

Events,

155/625

40/130


B. Random-effects model




ID


Study



0.92 (0.73, 1.15)

0.91 (0.70, 1.20)

OR (95% CI)

1.02 (0.79, 1.32)

0.52 (0.32, 0.87)

1.09 (0.83, 1.44)

415/1952

117/792

EGDT

155/625

Events,

40/130

103/405

537/2378

127/797

control

152/621

Events,

61/133

197/827

100.00

28.19

Weight

29.47

%

14.31

28.03

0.92 (0.73, 1.15)

0.91 (0.70, 1.20)

OR (95% CI)

1.02 (0.79, 1.32)

0.52 (0.32, 0.87)

1.09 (0.83, 1.44)

415/1952

117/792

EGDT

155/625

Events,

40/130

103/405






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)



Jones et al. (2010)



ID


Study

0.97 (0.86, 1.10)

1.17 (0.92, 1.48)

0.85 (0.54, 1.34)

0.93 (0.76, 1.16)

1.02 (0.80, 1.31)

OR (95% CI)

0.52 (0.31, 0.86)

723/2127

165/434

69/150

238/793

179/620

EGDT

72/130

Events,

902/2588

307/892

75/150

251/798

175/615

control

94/133

Events,

100.00

24.59

7.99

34.57

24.67

Weight

8.18

%

0.97 (0.86, 1.10)

1.17 (0.92, 1.48)

0.85 (0.54, 1.34)

0.93 (0.76, 1.16)

1.02 (0.80, 1.31)

OR (95% CI)

0.52 (0.31, 0.86)

723/2127

165/434

69/150

238/793

179/620

EGDT

72/130

Events,


B. Receipt of invasive mechanical ventilation (random-effects model)



ID

Jones et al. (2010)





Study

0.93 (0.77, 1.14)

OR (95% CI)

0.85 (0.54, 1.34)

0.93 (0.76, 1.16)

1.02 (0.80, 1.31)

0.52 (0.31, 0.86)

1.17 (0.92, 1.48)

723/2127

EGDT

69/150

238/793

179/620

72/130

165/434

Events,

902/2588

control

75/150

251/798

175/615

94/133

307/892

Events,

100.00

Weight

12.89

26.86

24.31

10.99

24.96

%

0.93 (0.77, 1.14)

OR (95% CI)

0.85 (0.54, 1.34)

0.93 (0.76, 1.16)

1.02 (0.80, 1.31)

0.52 (0.31, 0.86)

1.17 (0.92, 1.48)

723/2127

EGDT

69/150

238/793

179/620

72/130

165/434

Events,


8

C. Duration of invasive mechanical ventilation (days) (fixed-effect model)



Study

ID




0.48 (-0.34, 1.30)

-0.90 (-2.56, 0.76)

WMD (95% CI)

1.50 (0.18, 2.82)

0.00 (-3.73, 3.73)

0.40 (-1.04, 1.84)

723

165, 6.4 (8.4)

N, mean

(SD); EGDT

238, 6.2 (9)

72, 9 (11.4)

179, 6.6 (7.1)

902

307, 7.3 (9.4)

N, mean

(SD); control

251, 4.7 (5.4)

94, 9 (13.1)

175, 6.2 (6.7)

100.00

24.43

%

Weight

38.28

4.81

32.48

0.48 (-0.34, 1.30)

-0.90 (-2.56, 0.76)

WMD (95% CI)

1.50 (0.18, 2.82)

0.00 (-3.73, 3.73)

0.40 (-1.04, 1.84)

723

165, 6.4 (8.4)

N, mean

(SD); EGDT

238, 6.2 (9)

72, 9 (11.4)

179, 6.6 (7.1)

Favours EGDT Favours control 0-4 0 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)




Jones et al. (2010)


Study

ID


1.25 (1.10, 1.41)

0.56 (0.34, 0.92)

1.67 (1.34, 2.08)

1.29 (0.79, 2.10)

1.06 (0.84, 1.34)

OR (95% CI)

1.25 (1.00, 1.57)

1407/2135

48/130

605/793

108/150

269/439

Events,

EGDT

377/623

1577/2608

68/133

525/798

100/150

540/902

Events,

control

344/625

100.00

9.08

26.57

6.00

29.32

%

Weight

29.04

1.25 (1.10, 1.41)

0.56 (0.34, 0.92)

1.67 (1.34, 2.08)

1.29 (0.79, 2.10)

1.06 (0.84, 1.34)

OR (95% CI)

1.25 (1.00, 1.57)

1407/2135

48/130

605/793

108/150

269/439

Events,

EGDT

377/623


B. Receipt of vasopressors (random-effects model)



Study

Jones et al. (2010)



ID



1.15 (0.86, 1.53)

1.29 (0.79, 2.10)

1.25 (1.00, 1.57)

1.06 (0.84, 1.34)

OR (95% CI)

0.56 (0.34, 0.92)

1.67 (1.34, 2.08)

1407/2135

Events,

108/150

377/623

269/439

EGDT

48/130

605/793

1577/2608

Events,

100/150

344/625

540/902

control

68/133

525/798

100.00

%

15.10

23.30

23.04

Weight

15.10

23.46

1.15 (0.86, 1.53)

1.29 (0.79, 2.10)

1.25 (1.00, 1.57)

1.06 (0.84, 1.34)

OR (95% CI)

0.56 (0.34, 0.92)

1.67 (1.34, 2.08)

1407/2135

Events,

108/150

377/623

269/439

EGDT

48/130

605/793


10

C. Duration of vasopressors (days) (fixed-effect model)



ID



Study

0.09 (-0.12, 0.29)

0.10 (-0.13, 0.33)

WMD (95% CI)

0.10 (-0.39, 0.59)

-0.50 (-1.83, 0.83)

1407

269, 2.6 (1.6)

(SD); EGDT

605, 2.6 (4.9)

48, 1.9 (3.1)

N, mean

1577

540, 2.5 (1.6)

(SD); control

525, 2.5 (3.4)

68, 2.4 (4.2)

N, mean

100.00

79.23

Weight

18.31

2.46

%

0.09 (-0.12, 0.29)

0.10 (-0.13, 0.33)

WMD (95% CI)

0.10 (-0.39, 0.59)

-0.50 (-1.83, 0.83)

1407

269, 2.6 (1.6)

(SD); EGDT

605, 2.6 (4.9)

48, 1.9 (3.1)

N, mean




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


ID




Study

0.99 (0.81, 1.22)

OR (95% CI)

0.71 (0.36, 1.37)

0.99 (0.74, 1.31)

1.09 (0.79, 1.51)

206/1795

EGDT

12/382

106/793

88/620

Events,

224/2208

control

35/796

108/798

81/614

Events,

100.00

Weight

11.88

50.39

37.73

%

0.99 (0.81, 1.22)

OR (95% CI)

0.71 (0.36, 1.37)

0.99 (0.74, 1.31)

1.09 (0.79, 1.51)

206/1795

EGDT

12/382

106/793

88/620

Events,


B. Duration of renal replacement therapy (days)



ID


Study


-0.36 (-1.75, 1.03)

-0.50 (-5.16, 4.16)

WMD (95% CI)

-0.30 (-1.78, 1.18)

-1.50 (-8.86, 5.86)

206

106, 8.5 (17.1)

(SD); EGDT

88, 4.8 (5.5)

N, mean

12, 7.1 (10.8)

224

108, 9 (17.7)

(SD); control

81, 5.1 (4.3)

N, mean

35, 8.6 (12.4)

100.00

8.85

Weight

87.60

%

3.55

-0.36 (-1.75, 1.03)

-0.50 (-5.16, 4.16)

WMD (95% CI)

-0.30 (-1.78, 1.18)

-1.50 (-8.86, 5.86)

206

106, 8.5 (17.1)

(SD); EGDT

88, 4.8 (5.5)

N, mean

12, 7.1 (10.8)




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


12

Figure S7. Hospital length of stay for patients presenting to the emergency department with

septic shock (days)


ID




Study

Jones et al. (2010)


-0.28 (-1.18, 0.62)

WMD (95% CI)

1.10 (-1.51, 3.71)

0.20 (-3.12, 3.52)

-1.00 (-3.66, 1.66)

0.70 (-1.86, 3.26)

-0.70 (-1.90, 0.50)

2137

(SD); EGDT

625, 17.6 (23)

130, 13.2 (13.8)

793, 14.1 (17.3)

N, mean

150, 12.1 (11.7)

439, 11.1 (10)

2603

(SD); control

621, 16.5 (24)

133, 13 (13.7)

797, 15.1 (34.2)

N, mean

150, 11.4 (10.9)

902, 11.8 (11.5)

100.00

Weight

11.96

7.38

11.50

%

12.48

56.68

-0.28 (-1.18, 0.62)

WMD (95% CI)

1.10 (-1.51, 3.71)

0.20 (-3.12, 3.52)

-1.00 (-3.66, 1.66)

0.70 (-1.86, 3.26)

-0.70 (-1.90, 0.50)

2137

(SD); EGDT

625, 17.6 (23)

130, 13.2 (13.8)

793, 14.1 (17.3)

N, mean

150, 12.1 (11.7)

439, 11.1 (10)


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

.

.


Jones et al. (2010)


Yu et al. (2013)

EGDT Collaborative (2010)

ID

Subtotal (I-squared = 72.2%, p = 0.003)

de Oliveira et al. (2008)Wang et al. (2006)

Lu et al. (2014)


Tian et al. (2012)




Source: other/unclear

Source: ED

Study

0.94 (0.82, 1.07)

1.47 (0.82, 2.60)

0.98 (0.76, 1.26)

1.56 (0.42, 5.78)

0.46 (0.28, 0.74)

OR (95% CI)

0.61 (0.43, 0.86)

0.21 (0.07, 0.57)0.48 (0.11, 2.11)

1.06 (0.34, 3.35)

1.01 (0.88, 1.16)

3.55 (1.15, 10.99)

1.02 (0.80, 1.30)

1.17 (0.88, 1.55)

0.52 (0.31, 0.86)

572/2448

34/150

147/792

7/25

41/163

EGDT

77/314

6/514/16

7/40

495/2134

12/19

184/623

92/439

38/130

Events,

699/2930

25/150

150/796

5/25

64/151

control

117/329

20/517/17

7/42

582/2601

14/43

181/620

167/902

59/133

Events,

100.00

4.01

25.30

0.75

10.33

Weight

17.62

3.661.06

1.17

82.38

0.66

26.55

17.95

8.57

%

0.94 (0.82, 1.07)

1.47 (0.82, 2.60)

0.98 (0.76, 1.26)

1.56 (0.42, 5.78)

0.46 (0.28, 0.74)

OR (95% CI)

0.61 (0.43, 0.86)

0.21 (0.07, 0.57)0.48 (0.11, 2.11)

1.06 (0.34, 3.35)

1.01 (0.88, 1.16)

3.55 (1.15, 10.99)

1.02 (0.80, 1.30)

1.17 (0.88, 1.55)

0.52 (0.31, 0.86)

572/2448

34/150

147/792

7/25

41/163

EGDT

77/314

6/514/16

7/40

495/2134

12/19

184/623

92/439

38/130

Events,


14

B. Random-effects model by sub-group according to presenting source


.

.Overall (I-squared = 70.7%, p = 0.000)


Tian et al. (2012)



EGDT Collaborative (2010)

ID

Wang et al. (2006)

Yu et al. (2013)


Lu et al. (2014)

Source: other/unclear


de Oliveira et al. (2008)

Jones et al. (2010)Rivers et al. (2001)Source: ED

Study

0.87 (0.65, 1.17)

0.98 (0.76, 1.26)

3.55 (1.15, 10.99)

0.77 (0.35, 1.68)

1.17 (0.88, 1.55)

0.46 (0.28, 0.74)

OR (95% CI)

0.48 (0.11, 2.11)

1.56 (0.42, 5.78)

1.02 (0.80, 1.30)

1.06 (0.34, 3.35)

0.99 (0.79, 1.25)

0.21 (0.07, 0.57)

1.47 (0.82, 2.60)0.52 (0.31, 0.86)

572/2448

147/792

12/19

77/314

92/439

41/163

EGDT

4/16

7/25

184/623

7/40

495/2134

6/51

34/15038/130

Events,

699/2930

150/796

14/43

117/329

167/902

64/151

control

7/17

5/25

181/620

7/42

582/2601

20/51

25/15059/133

Events,

100.00

15.03

4.83

33.78

14.59

11.66

Weight

3.17

3.86

15.14

4.70

66.22

5.56

10.2611.20

%

0.87 (0.65, 1.17)

0.98 (0.76, 1.26)

3.55 (1.15, 10.99)

0.77 (0.35, 1.68)

1.17 (0.88, 1.55)

0.46 (0.28, 0.74)

OR (95% CI)

0.48 (0.11, 2.11)

1.56 (0.42, 5.78)

1.02 (0.80, 1.30)

1.06 (0.34, 3.35)

0.99 (0.79, 1.25)

0.21 (0.07, 0.57)

1.47 (0.82, 2.60)0.52 (0.31, 0.86)

572/2448

147/792

12/19

77/314

92/439

41/163

EGDT

4/16

7/25

184/623

7/40

495/2134

6/51

34/15038/130

Events,






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

Figure S9. Funnel plot for primary mortality outcome of individual studies

0.0

0.2

0.4

0.6

0.8

SE

of l

og(O

R)

0.2 0.5 1.0 2.0 5.0Odds ratio

Primary Secondary

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 ventilation, %

Duration of ventilation, days

Vasopressor support, %

Duration of vasopressors, days

RRT, % Duration of RRT, days

EGDT Control EGDT Control EGDT Control 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.

17

c Data presented for 10% lactate clearance group only. For the 30% lactate clearance group, duration of ventilation 4.0 ± 3.1 days.

18

Table S2. ICU admission and length of stay in ICU and hospital

Author ICU admission %

ICU length of stay days

Hospital length of stay 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.

19

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).

20

6. ACKNOWLEDGEMENTS

We are grateful to Ms Sue Rockliff (Librarian, The Queen Elizabeth Hospital, Adelaide, South

Australia) for assistance with the literature search.

21

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