Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Pan, 2019

SR and meta-analysis of RCTs

Literature search up to February 2018

A: Jones, 2010

B: Lyu, 2015

C: Puskarich, 2012

D: Tian, 2012

E: Wang 2014

F: Yu, 2013

G: Zhou 2017

Study design: RCT

Setting and Country:

Central South University Xiangya Hospital,

Changsha, Hunan China

Source of funding:

This work is partially supported by grants from The Provincial Science

Foundation of Hunan

Conflicts of interest:

The authors report no conflicts of interests.

Inclusion criteria SR:

1. adults with sepsis, severe sepsis, or septic shock

2. studies comparing combined lactate clearance-guided therapy with ScvO2-guided therapy

3. sufficient data available to calculate an relative ratio (RR) or mean difference (MD) with the 95% confidence interval

4. outcome measures that

included mortality incidences.

Exclusion criteria SR:

N.A.

7 studies included

Total N (intervention/ control):

A: 300 (150/150)

B: 100 (50/50)

C: 353 (178/175)

D: 62 (43/19)

E: 57 (26/31)

F: 50(25/25)

G: 360 (180/180)

Age and sex were not reported in SR.

Goals in lactate (LC) group:

A: LC>10%/6 h; UP >0.5 mL/kg/h; MAP>65mmHg

B: LC>10%/6 h; UP >0.5 mL/kg/h; MAP>65mmHg

C: LC>10%/6 h

D: LC>10%/6 h OR LC >30%/6 h; UP>0.5 mL/kg/h;

MAP>65mmHg

E: LC >50%/6 h; UP >0.5 mL/kg/h; MAP >65mmHg

F: LC>10%/6 h; UP >0.5 mL/kg/h; MAP>65mmHg

G: LC>30%/6h; CVP >8mmHg; MAP>65mmHg

Goals in ScvO₂>70% (control) group:

A: ScvO2>70%; UP>0.5 mL/kg/h; MAP>65mmHg

B: ScvO2>70%; UP>0.5 mL/kg/h; MAP>65mmHg

C: ScvO2>70%

D: ScvO2 >70%; UP >0.5 mL/kg/h; MAP >65mmHg

E: ScvO2>70%; UP>0.5 mL/kg/h; MAP>65mmHg

F: ScvO2>70%; UP>0.5 mL/kg/h; MAP>65mmHg

G: ScvO2>70%; CVP >8mmHg; MAP>65mmHg

End-point of follow-up:

A: in-hospital mortality

B: 28-day mortality

C: in-hospital mortality

D: 28-day mortality

E: 28-day mortality

F: 28-day mortality

G: 60-day mortality

For how many participants were no complete outcome data available?

(intervention/control)

Unclear.

Loss-to-follow-up:

Not reported

1. In-hospital mortality (primary outcome).

Risk ratio (95% CI):

A: 0.74 (0.46, 1.09)

B: 0.71 (0.47, 1.09)

C: 0.80 (0.52, 1.23)

D (1): 0.45 (0.21, 0.97)

D (2): 0.58 (0.30, 1.10)

E: 0.49 (0.24, 1.00)

F: 0.71 (0.26, 1.95)

G: 0.66 (0.45, 0.97)

Pooled effect (random effects model): 0.68 (0.56, 0.82) favouring LC. Heterogeneity (I²): 0%

2. Hospital length of stay

Mean difference (95% CI):

A: -0.70 (-3.26, 1.86)

F: -6.00 (-13.61, 1.61)

Pooled effect (random effects model): -1.24 (-3.66, 1.19) favouring LC.

Heterogeneity (I²): 40%

3. ICU length of stay

Mean difference (95% CI):

A: 0.30 (-1.50, 2.10)

B: -0.50 (-3.45, 2.45)

D (1): -3.37 (-7.04, 0.30)

D (2): -3.80 (6.98, -0.62)

E: -10.80 (-17.74, -3.86)

F:-2.00 (-3.96, -0.04)

G: 0.08 (-3.23, -0.05)

Pooled effect (random effects model): -1.64 (-3.23, -0.05) favouring LC.

Heterogeneity (I²): 70%

Lu, 2018

SR and meta-analysis of RCTs

Literature search up to February 2016

EGDT versus usual care

A: Rivers, 2001

B: Lin, 2006

C: Chen, 2007

D: Yan, 2010

E: Andrews, 2014

F: ARISE, 2014

G: ProCESS, 2014

H: ProMISe, 2015

EGDT versus lactate clearance–guided therapy

I: Jansen, 2010

J: Jones, 2010

K: Tian, 2012

L: Yu, 2013

M: Wang, 2014

Study design: RCT

Setting and Country:

Department of Blood Transfusion, Research Institute of Surgery, Daping

Hospital, Third Military Medical University, Chongqing, China

Source of funding and conflicts of interest:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Inclusion criteria SR:

1. study population comprised adult patients with severe sepsis or septic shock;

2. intervention group received a 6-hour protocol of EGDT;

3. comparison group received usual care or lactate clearance–guided therapy.

Exclusion criteria SR:

N.A.

13 studies included

N, condition, care unit, mean age, sex

A: 263, severe sepsis 47.1%, septic shock 52.9%, ED, age 67.1 ± 17.4, 50.8% male

B: 224, septic shock, ICU, age 67.2 ± 15.0, 59.3% male

C: 123, severe sepsis, ICU, age 51.3 ± 16.8, 66.2% male

D: 303, severe sepsis/septic shock, ICU, age 68.9 ± 15.6, 75.2% male

E: 103, severe sepsis, ED, age 35.2 ± 1.3, 52.8% male

F: 1588, septic shock, ED, age 62.7 ± 16.4, 60.2% male

G: 817, septic shock, ED, age 60 ± 16.4, 52.8% male

H: 1243, septic shock, ED, age 66.4 ± 14.6, 57% male

I: 135, severe sepsis 51.1%, septic shock 48.9%, ICU, age 62.0 ± 18.0, 62% male

J: 300, severe sepsis 18.4%, septic shock 81.6%, ED, age 61.6 ± 17.6, 53% male

K: 62, Septic shock, ICU, 46.2 ± 16.3, sex not reported

L: 50, severe sepsis 31%, septic shock 69%, ICU, age 59.0 ± 18.0, 76% male

M: 57, septic shock, ICU, age 52.0 ± 19.0, 61.3% male.

Groups were comparable at baseline.

Goals in EGDT group:

A: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5, mL/kg/h

B: CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

C: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

D: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

E: JVP ≥ 3 cm, MAP ≥ 65 mm Hg, Hb ≥ 7 g/dl

F: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

G: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

H: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

I: SaO₂ ≥ 92%, CVP 8-12 mm Hg, MAP 65-90 mm Hg, HR < 100/min, UO ≥ 0.5 mL/kg/h, Hb ≥7 g/dl

J: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5

mL/kg/h

K: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5

mL/kg/h

L: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

M: ScvO₂ ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

Goals in control group:

A: CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

B: usual care

C: CVP 8-12 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

D: CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

E: usual care

F: usual care

G: usual care

H: usual care

I: LC ≥ 20%, SaO₂ ≥ 92%, CVP 8-12 mm Hg, MAP 65-90 mm Hg, HR < 100/min, UO ≥ 0.5 mL/kg/h, Hb ≥ 7 g/dl

J: LC ≥ 20%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/ kg/h

K: LC ≥ 10% or 30%, ScvO2 ≥ 70%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/ kg/h

L: LC ≥ 10%, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/ kg/h

M: Lactate <2 mmol/L, CVP 8-12 mm Hg, SBP ≥ 90 mm Hg, MAP ≥ 65 mm Hg, UO ≥ 0.5 mL/kg/h

End-point of follow-up:

A: 60 days

B: hospital discharge

C: ICU discharge

D: ICU discharge

E: 28 days

F: 90 days

G: 90 days

H: 90 days

I: Hospital discharge

J: Hospital discharge

K: 28 days

L: 28 days

M: 28 days

For how many participants were no complete outcome data available?

(intervention/control)

No incomplete data.

Loss-to-follow-up:

Not reported

1. all-cause mortality at final follow-up. (primary outcome)

Risk ratio (95% CI):

A: 0.73 (0.56-0.96)

B: 0.75 (0.61-0.93)

C: 0.66 (0.43-1.01)

D: 0.69 (0.53-0.90)

E: 1.07 (0.83-1.39)

F: 0.98 (0.80-1.21)

G: 0.94 (0.78-1.15)

H: 1.10 (0.85-1.20)

Pooled effect (random effects model): 0.87 (0.77-0.98) favouring EGDT. Heterogeneity (I²): 55%

Differentiating per care unit:

In ICU 0.72 (0.62-0.84) favouring EGDT. Heterogeneity (I²): 0%

In ED 0.96 (0.86-1.06) favouring EGDT. Heterogeneity (I²): 21%

I: 1.52 (0.97-2.40)

J: 1.36 (0.86-2.16)

K: 1.94 (1.12-3.36)

L: 1.40 (0.51-3.82)

M: 2.04 (1.00-4.14)

Pooled effect (random effects model): 1.60 (1.24-2.06) favouring lactate-guided therapy. Heterogeneity (I²): 0%

Differentiating per care unit:

In ICU 1.71 (1.27-2.31) favouring lactate-guided. Heterogeneity (I²): 0%

In ED 1.36 (0.86-2.16) favouring lactate-guided (only 1 study).

2. Total volume of intravenous fluid in the first 6 hours.

Mean difference (95% CI):

A: 1.48 (0.82-2.14)

F: 0.25 (0.11-0.39)

G: 0.53 (0.27-0.78)

H: 0.20 (0.05-0.35)

Pooled effect (random effects model): 0.44 (0.18-0.71) favouring usual care. Heterogeneity (I²): 83%

3. Red-cell transfusion

Risk ratio (95% CI):

A: 3.15 (2.19-4.51)

F: 1.94 (1.43-2.64)

G: 1.77 (1.20-2.60)

H: 2.30 (1.44-3.67)

Pooled effect (random effects model): 2.22 (1.72-2.88) favouring usual care. Heterogeneity (I²): 47%

4. Vasopressor infusion

Risk ratio (95% CI):

A: 0.92 (0.63-1.35)

F: 1.15 (1.07-1.24)

G: 1.25 (1.09-1.42)

H: 1.14 (1.02-1.28)

Pooled effect (random effects model): 1.16 (1.10-1.23) favouring usual care. Heterogeneity (I²): 0%

5. Dobutamine use

Risk ratio (95% CI):

A: 18.42 (2.49-135.95)

F: 5.58 (3.72-9.19)

G: 7.27 (2.88-18.39)

H: 4.72 (3.08-7.23)

Pooled effect (random effects model): 5.45 (4.14-7.41) favouring usual care. Heterogeneity (I²): 0%

Facultative:

Brief description of author’s conclusion

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading

Sensitivity analyses (excluding small studies; excluding studies with short follow-up; excluding low quality studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question

Heterogeneity: clinical and statistical heterogeneity; explained versus unexplained (subgroupanalysis)

Chen, 2017

SR and meta-analysis of RCTs

Literature search up to August 2016

A: Tuchschmidt, 1992

B: Yu, 1993

C: Hayes, 1994

D: Gattinoni, 1995

E: Alía, 1999

F: Wang, 2006

G: The EDGT Collaborative Group, 2010

H: Lu, 2014

Study design: RCT

Setting and Country:

Sichuan University, Chengdu, Sichuang; Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi; Third Military Medical University, Chongqing, China

Source of funding and conflicts of interest:

This research was supported by the Foundation of the Health and Family Planning Commission Research Project of Jiangxi Province (grant no. 530096).

The authors declare no potential conflicts of interest.

Inclusion criteria:

1. Adult patients with severe sepsis and septic shock, treating with EGDT methods;

2. We used the standard EGDT, which was defined as a protocol resuscitation in accord with achieving specific therapeutic results in terms of CVP (8-12mmHg), MAP (65-90mmHg), UO (≥0.5ml/kg/h), and continuous monitoring to keep ScvO₂ (≥70%).

3. Usual care or other protocols were adopted in the control group based on the included trials.

4. We set the primary outcome measure as all-cause mortality at the early period for patient treatment during hospitalization (hospital or ICU mortality). All-cause mortality was defined as the time from the trial randomization to death from any cause.

Exclusion criteria: Non-RCTs or conference abstracts

17 studies were included. (10 were overlapping with SR Lu, 2018)

N, condition, care unit (age and sex not described)

A: 51, septic shock, ICU

B: 52, septic shock, ICU

C: 100, septic shock, ICU

D: 181, septic shock, ICU

E: 63, septic shock, ICU

F: 33, septic shock, ICU

G: 314, severe sepsis and septic shock, ICU

H: 82, septic shock, ICU

Goals in EGDT group:

A: CI>6 L/min/m², SBP>90 mm Hg

B: DO₂I>600 mL/min/m², SBP>100 mm Hg

C: CI>4.5 L/min/m², DO₂I>600 mL/min/m², VO₂>170 mL/min/m²

D: CI>4.5 L/min/m² or SvO₂>70%, MBP>65 mm Hg, CVP 8–12 mm Hg, UO>0.5 mL/kg/hr

E: DO₂I>600 mL/min/m², MBP>60 mm Hg

F: CVP 8–12 mm Hg, MAP>65 mm Hg, ScvO₂>70%, UO>0.5 mL/kg/hr

G: CVP 8–12 mm Hg, MAP>65 mm Hg, SBP>90mmHg, UO>0.5 mL/kg/hr, ScvO₂>70%

H: ITBVI 850-1500 mL/m², MAP≥65 mmHg

Goals in control group:

A: CI>3 L/min/m², SBP>90 mm Hg

B: DO₂I 450–550 mL/min/m²

C: Usual care

D: CI 2.5–3.5 L/min/m², MBP>65 mm Hg, CVP 8–12 mm Hg, UO>0.5 mL/kg/hr

E: DO₂I>330 mL/min/m², MBP>60 mm Hg

F: Usual care

G: CVP 8–12 mm Hg, MAP >65 mm Hg, SBP>90mmHg, UO>0.5 mL/kg/hr

H: CVP 8–12 mm Hg, MAP >65 mm Hg, ScvO₂>70%, UO>0.5 mL/kg/hr

End-point of follow-up:

A: hospital discharge

B: 30 days

C: hospital discharge

D: 180 days

E: ICU discharge

F: 14 days

G: 28 days

H: hospital discharge

Loss-to-follow-up:

Not reported

Hospital/ICU mortality at final follow-up (primary outcome)

Risk ratio (95% CI):

A: 2.56 (1.20-5.49)

B: 1.00 (0.51-1.94)

C: 1.59 (1.00-2.52)

D: 0.95 (0.77-1.17)

E: 0.72 (0.48-1.08)

F: 0.61 (0.22-1.69)

G: 0.58 (0.42-0.81)

H: 0.95 (0.37-2.47)

Pooled effect (random effects model): 0.96 (0.71-1.30) favouring EGDT. Heterogeneity (I²): 68%

Jiang, 2016

SR and meta-analysis of RCTs

Literature search up to April 2015

A: ARISE, 2014

B: ProCESS, 2014

C: ProMISe, 2015

Study design: RCT

Setting and Country:

Several institutes in Italy

Source of funding and conflicts of interest:

none declared

Inclusion criteria:

1. Patients with severe sepsis or septic shock.

2. EGDT versus usual care

Exclusion criteria: Not reported

4 studies were included, 3 of which were overlapping with other SRs.

Details of the included studies are described under the SR by Lu, 2018

Details of the included studies are described under the SR by Lu, 2018

Details of the included studies are described under the SR by Lu, 2018

Details of the included studies are described under the SR by Lu, 2018

Hospital length of stay

Mean difference (95% CI):

A: 0.10 (-0.59-0.79)

B: 0.40 (-0.44-1.24)

C: -0.70 (-1.82-0.42)

Pooled effect: see below

Coccolini, 2016

SR and meta-analysis of RCTs

Literature search up to 2016

A: Rivers, 2001

B: ARISE, 2014

C: ProCESS, 2014

D: ProMISe, 2015

Study design: RCT

Setting and Country:

Several institutes in Italy

Source of funding and conflicts of interest:

none declared

Inclusion criteria:

Studies analyzing patients

with early septic shock randomly assigned to receive

either EGDT or standard care.

Exclusion criteria: Not reported

4 studies were included, 3 of which were overlapping with other SRs.

Details of the included study are described under the SR by Lu, 2018

Details of the included study are described under the SR by Lu, 2018

Details of the included study are described under the SR by Lu, 2018

Details of the included study are described under the SR by Lu, 2018

Hospital length of stay

Mean difference (95% CI):

-0.50 (-1.39-0.39)

Pooled effect (random effects model) including Jiang, 2016:

0.04 (-0.43-0.52) favouring usual care.

Heterogeneity (I²): 0%

Angus, 2015

SR and meta-analysis of RCTs

Literature search up to 2016

A: ARISE, 2014

B: ProCESS, 2014

C: ProMISe, 2015

D: Jones, 2010

Study design: RCT

Setting and Country:

Multi-center from USA, UK, Australia

Source of funding and conflicts of interest:

none declared

Inclusion criteria:

RCTs conducted in adult or paediatric patient populations with septic shock that compared EGDT with either usual care or another resuscitation

strategy that did not incorporate EGDT.

Exclusion criteria: Studies reporting only physiological end-points, solely descriptive or non-randomised and any studies published before 2000.

11 studies were included

Details of the relevant included study are described under the SR by Lu, 2018

Details of the studies are described under the SR by Lu, 2018

Details of the studies are described under the SR by Lu, 2018

Details of the studies are described under the SR by Lu, 2018

ICU length of stay

Mean difference (95% CI):

A: 0.10 (-0.59-0.79)

B: 0.20 (-0.57-0.97)

C: -0.70 (-1.82-0.42)

D: -0.30 (-2.10-1.50))

Pooled effect (random effects model):

-0.02 (-0.47-0.43) favouring EGDT.

Heterogeneity (I²): 0%

Simpson, 2016

SR and meta-analysis of RCTs

Literature search up to May 2015

A: Rivers, 2001

B: Chen, 2007

C: EGDT collaborative, 2010

D: ProCESS, 2014

E: ARISE, 2014

F: ProMISe, 2015

Study design: RCT

Setting and Country:

OpenMetaAnalysis from Kansas University School of Medicine – Wichita, Kansas, USA

Source of funding and conflicts of interest:

This project was supported by the Department of Internal Medicine at the Kansas University School of Medicine – Wichita

Conflict of interest: not specified.

Inclusion criteria:

We included trials that randomly allocated patients to EGDT. We required EGDT to include goals for central venous pressure and central venous oxygen saturation (ScvO2) and for goals to be completed within 6 hours. We did not require blinding of participants.

Exclusion criteria: None.

6 studies were included

Details of the studies are described under the SRs by Lu, 2018 and Chen, 2017

Details of the studies are described under the SRs by Lu, 2018 and Chen, 2017

Details of the studies are described under the SRs by Lu, 2018 and Chen, 2017

Details of the studies are described under the SRs by Lu, 2018 and Chen, 2017

Mortality

Subgroups were made based on mortality in the control group (values were slightly different than in other SRs).

RR (95% CI) with >40% mortality in the control group:

A: 0.66 (0.47-0.91)

B: 066 (0.43-1.01)

C: 0.69 (0.53-0.90)

Pooled, random effects model:

0.67 (0.56-0.81) favouring EGDT.

Heterogeneity (I²): 0%

RR (95% CI) with <30% mortality in the control group:

D: 1.11 (0.85-1.45)

E: 0.93 (0.73-1.17)

F: 1.02 (0.86-1.21)

Pooled, random effects model:

1.01 (0.89-1.14)

Heterogeneity (I²): 0%

Pooled effect total:

0.85 (0.71-1.02) favouring EGDT

Heterogeneity (I²): 64%

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Asfar, 2014

SEPSISPAM ClinicalTrials

.gov number

NCT01149278

Type of study: RCT

Setting and country: multicentre, open-label trial in 29 centers in France

Funding and conflicts of interest: Supported by the French Ministry of Health.

Dr. Asfar reports receiving lecture fees from LFB; Dr. Meziani, receiving grant support from LFB; Dr. Mira, receiving honoraria and travel support from LFB and Eisai and honoraria from AstraZeneca; Dr. Weiss, receiving lecture fees from Gore; Dr. Gonzalez, receiving travel support from Merck Sharp and Dohme and Novartis; and Dr. Mercat, receiving grant support from Covidien, Maquet, and General Electric, consulting fees from Air Liquide Medical Systems, and fees for serving on a steering committee from Faron Pharmaceuticals and being named as an inventor on a patent related to methods of evaluating a patient for positive end-expiratory pressure therapy (US 12/834,354), which is to be licensed to General Electric.

Condition: septic shock

Domain: ICU

Ventilated: 75%

Inclusion criteria:

Older than 18 years of age, septic shock that was refractory to fluid resuscitation, if they required vasopressors at a minimum infusion rate of 0.1 μg per kilogram per minute, and if they were evaluated within 6 hours after the initiation of vasopressors.

Exclusion criteria:

Legal protection, no affiliation with the French health care system, pregnancy, recent participation in another biomedical/ interventional study with mortality as the primary end point, or an investigator’s decision not to resuscitate.

N, age, sex:

Intervention: 388, 65±13, 68.8% male

Control: 388, 65±15, 64.4% male

Groups were comparable at baseline

Intervention goals:

targeting a mean arterial pressure of 80 to 85 mm Hg

Control goals:

targeting a mean arterial

pressure of 65 to 70 mm Hg

Length of follow-up:

90 days

Incomplete outcome data:

Not described

28-day mortality (primary outcome)

Risk ratio (95% confidence interval)

1.08 (0.89, 1.30) favouring low MAP. P=0.57

90-day mortality

Risk ratio (95% CI)

1.04 (0.88, 1.22) favouring low MAP. P=0.74

Cumulative fluid intake (5 days)

Mean difference (95% CI)

0.50 (-0.37, 1.37) favouring low MAP. P=0.89

ICU length of stay

Risk ratio (95% CI)

0.00 (-1.31, 1.31). P=0.60

Chen, 2015

NCT 02473718

Type of study: RCT pilot

Setting and country:

Academic tertiary care hospital, Washington University School of Medicine, USA.

Funding and conflicts of interest:

No funding was received for this study.

No conflict of interest declared. M. H. K. is supported by the Barnes-Jewish Hospital Foundation.

Condition: septic shock

Domain: ICU

Ventilated: 70%

Inclusion criteria:

Adult patients with septic shock who presented to the medical ICU; septic shock as the primary cause of hypotension and hypotension necessitating vasoactive drugs that persisted for at least 12 h after initial adequate IV fluid administration and at the time of enrolment.

Exclusion criteria:

Prior enrolment in the study, age <18 years, presence of end-stage renal disease necessitating hemodialysis or peritoneal dialysis as an outpatient immediately prior to admission, pregnancy, or goals of care consistent with comfort measures only.

N, age, sex:

I: 41, 58 years old, 49% male.

C: 41, 60 years old, 51% male.

Groups were comparable at baseline

Intervention (TFM):

Fluid challenge by passive leg raise, or, if the primary team had already decided to administer a fluid bolus or perform an RBC transfusion, this was used in lieu of a passive leg raise.

Fluid responders received fluid resuscitation, fluid non-responders received targeted fluid minimization

Control:

Usual care.

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. In-hospital mortality

Intervention: 56.1%,

usual care: 48.8%, P=0.51

RR (95% CI):

1,15 (0.76, 1.74) favouring usual care.

2. Cumulative study fluid (day 5, ml)

I: 6244±2512;

C: 8690±6656;

P=0.26

Mean difference (95% CI)

-2446.00 (-4950.36, 58.36)

Kleine populatie

Garg, 2016

Type of study: RCT pilot

Setting and country:

Prospective, randomized study was carried out in the ICU at Harma University of Health Sciences, Rohtak, Haryana, India

Funding and conflicts of interest:

No financial support, no conflicts of interest.

Condition: septic shock

Domain: ICU

Ventilated: all

Inclusion criteria:

Two out of four criteria for systemic inflammatory response syndrome, probable or suspected septic etiology, systolic blood pressure <90 mmHg or mean arterial pressure (MAP) <70 mmHg despite adequate fluid challenge (20 ml/kg of normal saline infused over half hour), and positive pressure ventilation.

Exclusion criteria:

Pregnancy or other causes of raised intra‑abdominal pressure, patients in whom USG could not be done because of poor echo window or dressings, acute coronary syndrome, cardiac dysrhyth-mias (as a primary diagnosis), congestive heart failure, pulmonary embolism, status asthmaticus, contraindication to central venous catheterization, burn injury, requirement of immediate surgery, and do‑not-resuscitate status

N, age, sex:

I: 18, 37.4±15.5, 56% male

C: 18, 44.5±18.7, 44% male

Groups were comparable at baseline

Intervention (IVC CI) goals:

MAP ≥65 mmHg

IVC CI <20%

Control (CVP) goals:

MAP ≥65 mmHg

CVP >12 mmHg

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

Mortality (28 days)

I: 11/18 (61%)

C: 9/18 (50%)

RR (95% CI):

1.22 (0.68, 2.21)

Kleine populatie en beduidend jonger dan in andere studies.

Kuan, 2016

Type of study: RCT

Setting and country:

Open-label, single-center study from the ED of National University Hospital, a tertiary university-affiliated hospital in Singapore

Funding and conflicts of interest:

This work was supported by the National University Health System Clinician Research Grant (FY2011) and the National Medical Research Council New Investigator Grant (NIG11may049) to Dr. Kuan. Dr. Kuan reports receiving grant support from the National Medical Research Council Transition Award. Dr. Lu’s institution (Singapore Clinical Research Institute) received funding from the National University Health System Clinician Research Grant (FY2011) in statistical analysis and preparation of the article.

Cheetah Medical did not participate in the design of the study or the decision to submit this article for publication.

Condition: severe sepsis or septic shock

Domain: ED

Ventilated: 15%

Inclusion criteria:

Patients with a serum lactate level greater than or equal to 3 mmol/L with suspected infection and fulfilled at least 2 systemic inflammatory response syndrome criteria: (1) body temperature greater than 38.3 or less than 36.0˚C; (2) pulse rate greater than 90 beats/min; (3) respiratory rate greater than 20 breaths/min or PaCO₂ less than 32 mm Hg; and (4) WBC count greater than 12.0*10⁹/L or less than 4.0*10⁹/L.

Exclusion criteria:

pregnancy, younger than 21 years, prisoners, do-not-attempt resuscitation status, known severe aortic insufficiency or severe anatomic abnormalities of the thoracic aorta, requirement for immediate surgery, previous above- or below-knee amputation, inability to do passive leg raising (eg, ankylosis of hip joint, severe sciatica), and treating physician deemed aggressive care unsuitable; individuals who received or were receiving β-agonist therapy within the last 4 hours, those who received 200 mL of crystalloids out-of-hospital, those unable to provide informed consent, and a primary diagnosis of trauma, burns, active seizures, acute cerebral vascular accident, acute coronary syndrome, status asthmaticus, major cardiac arrhythmias, active gastrointestinal hemorrhage, seizure, or drug overdose.

N, age, sex:

I: 61, 66.6±14.9, 50.8% male

C: 61, 64.3±14.6, 65.6% male

Groups were comparable at baseline

Intervention:

ΔSVI ≤ 10% and

65 ≤ MAP < 90 mm Hg.

(ΔSVI, Change in stroke volume index)

Control:

Usual care, MAP greater than or equal to 65 mm Hg

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. Primary outcome:

Lactate clearance greater than 20% at 3 hours after the commencement of resuscitation.

Risk ratio (95% CI):

0.96 (0.77, 1.19) favouring intervention.

2. Hospital mortality

I: 8/31 (13.1%)

C: 6/61 (9.8%)

Risk ratio (95% CI):

1.33 (0.49, 3.61) favouring control

3. ICU mortality

I: 6/22 (27.3%)

C: 4/23 (17.4%)

Risk ratio (95% CI):

1.57 (0.51, 4.82) favouring control

4. 28-day mortality

I: 6/61 (9.8%)

C: 6/61 (9.8%)

Risk ratio (95% CI):

1.00 (0.34 to 2.93)

5. ICU length of stay (h)

I: 96.0 (IQR 72.0 to 120.0)

C: 96.0 (IQR 60.0 to 144.0)

Mean difference (95% CI):

0 (-35.0, 42.0)

6. hospital length of stay (days)

I: 7.0 (IQR 3.0 to 12.0)

C: 7.0 (IQR 4.0 to 14.0)

Mean difference (95% CI):

0 (-3, 3)

Lanspa, 2018

Type of study: RCT (pilot)

Setting and country: single-center feasibility RCT in Utah, USA

Funding and conflicts of interest: The Easton Family Fund and Intermountain Research and Medical Foundation provided funding for this research. Neither body had any role in study design, implementation, data interpretation or manuscript preparation.

The authors declare that they have no competing interests

Condition: septic shock

Domain: ICU/ED

Ventilated: 20%

Inclusion criteria:

adult patients with septic shock and either the presence of or intention to place a central venous catheter and an arterial catheter.

Exclusion criteria:

patients who were moribund, pregnant, incarcerated, or for whom immediate surgery was planned; patients in whom the protocol could not be performed either due to clinician or patient directives, or in patients with chest or abdominal pathology that would prevent a limited TTE.

N, age, sex:

I: 15, 69±11.9, 47% male.

C: 15, 64±19.6, 53% male.

Groups were comparable at baseline.

Intervention (ECHO) goals:

Assessment consisted of measuring a lactate and performing a focused TTE to assess the inferior vena cava (IVC) collapsibility and myocardial function.

1. MAP ≥ 65 mmHg

If not, IVC was assessed by ECHO for collapsibility (collapsing if the maximum diameter was < 5 mm or if vena cava collapsibility index (VCCI), defined as the difference in diameter during a respiratory cycle divided by the maximum diameter, was > 50%). Collapsing: fluid, not collapsing: norepinephrine.

2. Lactate clearance > 10%

If not, assessment of myocardial dysfunction by ECHO. If so, adjustment of MAP with norepinephrine or dobutamine.

Control (EGDT) goals:

CVP 8-12 mmHg

MAP ≥ 65 mmHg

ScVO2 ≥ 70%.

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

Mortality (28 days)

I: 5/15 (33%)

C: 3/15 (20%)

P=0.68

RR (95% CI):

1.67 (0.48, 5,76)

No experimental separation was observed in this randomized, controlled feasibility trial. Early lactate clearance, coupled with substantial fluid administration before randomization, suggests that patients were already resuscitated before arrival in the ICU.

Kleine populatie

Lu, 2015

Type of study: RCT

Setting and country: single-center study in Northern Jiangsu People's Hospital, Yangzhou, China

Funding and conflicts of interest:

The authors have no conflict of interest to declare.

The authors thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. This work was supported by funding from “333 high-level personnel training project” in Jiangsu Province.

Condition: severe sepsis or septic shock

Domain: ICU/ED

Ventilated: 74%

Inclusion criteria:

Patients 18 years or older that had been diagnosed with septic shock: systolic blood pressure less than 90 mm Hg, a systolic blood pressure decrease greater than 40 mm Hg, or less than 2 SDs below normal for age in the absence of other causes of hypotension.

Exclusion criteria:

Patients with myocardial infarction, pregnancy, immune-suppressive therapy, patients that were terminally ill, or that had ever received fluid resuscitation in another hospital.

N, age, sex:

I: 53, 60.8±15.1, 66% male

C: 61.5±14.4, 63% male

Groups were comparable at baseline

Intervention (PiCCO) goals:

Treatment with the improved sepsis bundles was guided by PiCCO measurements. However, patients received interventions with vasoactive drugs, antibiotics, and oxygen therapy following the same guidelines as the control group.

PiCCO: Pulse-indicated continuous cardiac output

Control (EGDT) goals:

CVP 8-12 mmHg

MAP ≥ 65 mmHg

urinary production ≥ 0.5 mL/kg/h

ScVO2 ≥ 70%.

Length of follow-up:

Unclear

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. Hospital mortality

Intervention 13/53 (24.5%)

Control 15/52 (28.8%)

RR (95% CI)

0.85 (0.45, 1.61) favouring PiCCO

P=0.617

2. ICU mortality

Intervention 11/53 (20.8%)

Control 13/52 (25%)

RR (95% CI)

0.83 (0.41, 1.68) favouring PiCCO

P=0.604

Nardi, 2013

Type of study: RCT (pilot)

Setting and country: single-centre, randomised, nonblinded pilot trial at the ICU of Raymond Poincare´ Hospital, Garches, France

Funding and conflicts of interest:

Funding not described.

The authors have no conflicts of interest to disclose.

Condition: severe sepsis or septic shock

Domain: ICU

Ventilated: some, number not specified

Inclusion criteria:

Subjects with suspected or confirmed source of infection, 18 years of age or older, with two or more Systemic Immune Response Syndrome criteria, and one of the following signs of hypoperfusion: (1) systolic blood pressure of 90 mmHg or less; (2) arterial lactates of 4 mmol/l or more; (3) mottled skin; (4) urine output of less than 30 ml/h for at least 1 h; and (5) mental confusion.

Exclusion criteria:

pregnant women, brain dead patients, and the decision to withhold or withdraw life-supporting treatments

N, age, sex:

I: 15, 59±15, 73% male.

C: 15, 63±15, 67% male.

Groups were comparable at baseline

Intervention goals:

In addition to control goals, Skeletal Muscle Tissue Oxygenation (StO₂) was increased to 80% or higher in at least 2 muscular sites by transfusion and/or dobutamine infusion

Control goals:

CVP 8-12 mm Hg

MBP 65-80 mm Hg

ScVO₂≥70%

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. mortality (28 days)

I: 5/15 (33%)

C: 4/15 (27%)

RR (95% CI)

1.25 (0.41, 3.77) favouring control. P=1.0

2. mortality at discharge

I: 6/15 (40%)

C: 4/15 (27%)

RR (95% CI)

1.83 (0.39, 8.57) favouring control. P=0.7

3. ICU length of stay (days)

Mean difference (95% CI)

-4.50 (-25.1, 16.1) favouring experimental intervention. P=0.7

4. Cumulative fluid loading (ml)

Mean difference (95% CI)

137 (-452, 726) favouring control intervention. P=0.17

Kleine populatie

Nardi, 2018

NCT 00167596.

Type of study: RCT

Setting and country: multicentre,

randomised, non-blinded phase II/III trial in France (2x), Greece, Spain and Germany.

Funding and conflicts of interest:

Funded by University of Versailles SQY, Assistance Publique Hôpitaux de Paris and

Hutchinson Technology.

The authors have no conflicts of interest to disclose.

Condition: severe sepsis or septic shock

Domain: ICU

Ventilated: all (?)

Inclusion criteria:

Patients with suspected or confirmed sources of infection, 18 years or older, two or more of the Systemic Immune Response Syndrome criteria and exhibited at least one of the following signs of tissue hypoperfusion: (1) a systolic blood pressure of 90 mm Hg or less; (2) arterial lactate level of 4 mmol/L or more; (3) mottled skin; (4) urine output below 30 mL/hour for at least 1 hour; and (5) altered mental status.

Exclusion criteria:

Pregnant women, brain-dead patients and patients who decided to withhold or withdraw from life-supporting treatments.

N, age, sex:

I: 54, 65.6±16, 67% male.

C: 49, 60.8±18, 67% male.

Groups were comparable at baseline

Intervention goals:

In addition to control goals, Skeletal Muscle Tissue Oxygenation (StO₂) was increased to 80% or higher in at least 2 muscular sites by transfusion and/or dobutamine infusion

Control goals:

CVP 8-12 mm Hg

MBP 65-80 mm Hg

ScVO₂≥70%

Length of follow-up:

30 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

Mortality (30 days)

I: 17/54 (32%)

C: 15/49 (31%)

RR (95% CI)

1.03 (0.58, 1.83) favouring control. P=0.9

Mortality pooled with pilot (28/30 days):

RR (95% CI)

1.07 (0.64, 1.79) favouring control

Palizas, 2009

Type of study: RCT

Setting and country: 6 closed intensive care units from Chile, Argentina and Brazil.

Funding and conflicts of interest:

The study was funded by institutional (departmental) grants for each

participating center. The authors declare that they have no competing interests.

Condition: septic shock

Domain: ICU

Ventilated: not reported

Inclusion criteria:

Adult patients with septic shock according to the ACCP/SCCM Consensus Conference within 48 hours of ICU admission were considered and selected if they were in a 12-hour time window.

Exclusion criteria:

Terminal illness with the patient expected to die within 28 days, irreversible neurologic impairment, and contraindication for nasogastric tube placement.

N, age, sex:

I: 64, 59.9±15.9, 52% male.

C: 66, 57.4±15.9, 64% male.

Groups were comparable at baseline

Intervention (gastric tonometry):

All patients were initially treated to normalize macrohemodynamic parameters for 2 to 4 hours, especially a MAP ≥70 mm Hg

Subsequently, therapy aimed at a gastric mucosal pHi of 7.32 or greater

Control (cardiac index):

All patients were initially treated to normalize macrohemodynamic parameters for 2 to 4 hours, especially a MAP ≥70 mm Hg

Subsequently, therapy aimed at a cardiac index of 3.0 L/min/m² or more

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. 28-day mortality

Gastric tonometry 30.3%, cardiac index 28.1%. P = 0.98

RR (95% CI)

0.90 (0.42, 1.92) favouring cardiac index group.

2. ICU length of stay

Gastric tonometry 12.6 ± 8.2 versus. cardiac index 16 ± 12.4 days, P = 0.07

Mean difference (95% CI)

-3.40 (-7.00, 0.20)

Richard, 2015

NCT

01972828

Type of study: RCT

Setting and country:

Single-center trial at the ICU in a hospital in Lyon, France.

Funding and conflicts of interest:

This study was funded by the following grant: Appel d’offre jeune chercheur 2005 des Hospices Civils de Lyon, Lyon France.

The authors declare that they have no competing interests

Condition: septic shock

Domain: ICU

Ventilated: 77%

Inclusion criteria:

18 years or older with septic shock, who had received intravascular fluid loading of at least 25 mL.kg-1 body weight, with hypotension onset less than 6 hours before inclusion. An amendment to the original protocol extended the time from hypotension onset to 12 hours after inclusion of the first three patients.

Exclusion criteria:

pregnancy, acute coronary syndrome, acute cerebral event during the previous 30 days, cardiogenic pulmonary edema, contraindication to central venous or femoral artery catheterization, uncontrolled haemorrhage, burn injury on more than 20% of the body surface, trauma, requirement for immediate surgery or radiological procedure, previous inclusion in present study, inclusion in another randomized controlled trial during the same ICU stay, advance directives to withhold or withdraw life-sustaining treatment, lack of written informed consent by patient or next of kin, lack of affiliation to social security as required by French regulation, patient under a legal protective measure.

N, age, sex:

I: 30, 65 years old, 70% male.

C: 30, 64 years old, 73% male.

Groups were comparable at baseline.

Intervention goals:

Preload dependence-driven fluid management.

PPV<13%

ΔSVI<10%

65≤MAP≤75 mm Hg

Ht>20%

2.5≤CI≤3 L/min/m²

Control goals:

CVP-driven fluid management

CVP≥8 mm Hg

65≤MAP≤75 mm Hg

Ht>20%

2.5≤CI≤3 L/min/m²

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. Mortality (28 days)

RR (95% CI):

0.50 (0.24, 1.06) favouring preload strategy. P=0.10

2. ICU length of stay (days)

Mean difference (95% CI)

4.00 (-2.77, 10.77). P=0.55

Su, 2018

Type of study: RCT

Setting and country: multicenter study from

ICUs at 14 hospitals in China

Funding and conflicts of interest:

No funding applicable. All of the authors declare that they have no competing interests

Condition: severe sepsis or septic shock

Domain: ICU

Ventilated: not specified

Inclusion criteria:

2 or more of the following signs during their 1st 24h of ICU stay:

i) temperature >38 ˚C or <36˚C; ii) pulse rate >90 beats/min; iii) respiratory rate >20 breaths/min or hyperventilation with partial pressure of arterial carbon dioxide (PaCO₂) <32 mmHg; iv) white blood cell count >12,000 μL^-1 or <4000 μL^-1; v) and>10% immature cells. Sepsis with sepsis-induced organ dysfunction/tissue hypoperfusion or persistently low BP following the administration of intravenous fluids was required.

Exclusion criteria:

i) <18 years of age; ii) pregnant or lactating women; iii) Exhibited central venous or arterial catheter contraindications; iv) were invasive/noninvasive ventilator-dependent with a cardiac function level of IV according to the standard of New York Heart Disease Academy (NYHA), had severe liver failure (Child C grade), were on long-term blood / peritoneal dialysis therapy or were receiving long-term immune suppression therapy (radiotherapy and chemotherapy); v) had an end-stage malignant tumor; vi) died within 24 hours of admittance to the ICU, refused to participate in the study, or stopped treatment during the period of observation; or vii) exhibited other factors that may have affected assessments of the relevant monitoring indicators.

N, age, sex:

I: 114, 63±17, 56% male.

C: 114, 62±17, 69% male.

Groups were comparable at baseline.

Intervention

(P(v-a)CO2/C(a-v)O2) goals:

P(v-a)CO2/C(a-v)O2 target value was set at ≤ 1.8.

Volume responsiveness assessment was performed if the P(v-a)CO2/C(a-v)O2 did not reach 1.8. Fluid resuscitation was continued if positive; otherwise inotropic agents were used. Oxygen consumption reduction was also considered, including lowering the body temperature, sedatives and analgesia.

Control (ScvO2) goals:

Venous oxygen saturation (ScvO2) ≥70%.

Length of follow-up:

60 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. Mortality (28 days)

I: 32/114 (29.6%)

C: 25/114 (24.0%)

RR (95% CI):

1.28 (0.81, 2.02) favouring ScvO2. P=0.35

2. Mortality (60 days)

I: 38/114 (33.3%)

C: 39/114 (34.2%)

RR (95% CI):

0.97 (0.68, 1.40) favouring P(v-a)CO2/C(av)O2. P=0.89

3. ICU length of stay (days)

I: 6 (IQR 4-13)

C: 7 (IQR 3-15)

Mean difference (95% CI):

-1.00 (-3.04, 1.04) favouring P(v-a)CO2/C(av)O2. P=0.89

4. Hospital length of stay (days)

I: 16 (IQR 8-32)

C: 18 (IQR 8-33)

Mean difference (95% CI):

-2.00 (-6.71, 2.71) favouring P(v-a)CO2/C(av)O2. P=0.6

Trof, 2012

NL

14119.029.06

Type of study: RCT

Setting and country:

Prospective, randomized, nonblinded clinical trial conducted in intensive care units (ICUs) of a university hospital and a large teaching hospital in The Netherlands.

Funding and conflicts of interest:

This study has been supported by an unrestricted research grant by Pulsion Medical Systems AG, Munich, Germany.

Dr. Trof received an unrestricted research grant from Pulsion Medical Systems, Germany. The remaining authors have not disclosed any potential conflicts of interest.

Condition: septic shock

Domain: ICU

Ventilated: all

Inclusion criteria:

Septic shock was defined by shock plus two or more of the following for systemic inflammatory response syndrome criteria: abnormal body temperature (>38˚C, <36˚C), tachycardia (>90 beats/min), mechanical ventilation, and abnormal white blood cell counts (≤4 or ≥12 * 10⁹/L or >10% immature bands) plus a clinically evident and/or microbiologically proven focus on infection.

Exclusion criteria:

Age <18 or >80 yrs, pregnancy, preterminal illness with life expectancy <24 hrs, therapeutic hypothermia after cardiac arrest, traumatic brain injury, absence of mechanical ventilation, known (unrepaired) cardiac or vascular aneurysms, bifemoral vascular surgery, known pulmonary hypertension (defined as mean pulmonary artery pressure >50 mm Hg), or absence of informed consent.

N, age, sex:

I: 38, 67±19, 53% male.

C: 34, 67±15, 53% male.

Groups were comparable at baseline.

Intervention (TPTD) goals:

EVLW≥10mL/kg

GEDVI≥850mL/m²

TPTD: transpulmonary thermodilution

EVLW: extravascular lung water index;

GEDWI: global end-diastolic volume index

Control (PAC) goals:

PCWP≥18 mmHG, PEEP<10cmH₂O

or

PCWP≥20 mmHG, PEEP≥10cmH₂O

PAC: pulmonary artery catheter;

PCWP: pulmonary capillary wedge pressure;

PEEP: positive end-expiratory pressure

Length of follow-up:

28 days

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. ICU length of stay (days)

I: 11 (IQR 17)

C: 15 (IQR 15)

Mean difference (95% CI):

-4.00 (-9.47, 1.47) favouring TPTD. P=0.39

2. Hospital length of stay (days)

I: 27 (IQR 42)

C: 25 (IQR 25)

Mean difference (95% CI):

2.00 (-9.68, 13.68) favouring PAC. P=0.60

3. Mortality (28 days)

I: 16/38 (42%)

C: 13/34 (38%)

RR (95% CI):

1.10 (0.62, 1.94) favouring PAC. P=0.87

Yao, 2017

Type of study: RCT

Setting and country:

Hospital in Shandong, China

Funding and conflicts of interest:

Not stated.

Condition: septic shock

Domain: ICU

Ventilated: all (?)

Inclusion criteria:

Septic shock.

Exclusion criteria:

Not described.

N, age, sex:

I: 44, 64±9, 52% male.

C: 44, 63±7, 55% male.

Groups were comparable at baseline.

Intervention (PiCCO) goals:

ELWI 7-10 ml/kg

ITBI 850-1000 ml/m²

ELWI: extra lung water index

Control goals:

CVP 8-12 mm Hg

Length of follow-up:

Not described

Loss-to-follow-up:

Not described

Incomplete outcome data:

Not described

1. ICU length of stay (days):

I: 6.32±2.13

C: 10.36±3.25

P<0.05

Mean difference (95% CI):

-0.40 (-0.50, -0.30)

2. Fluid volume (ml):

I: 1734±253

C: 2135±205

P<0.05

Mean difference (95% CI):

-0.40 (-0.50, -0.30)

Yu, 2007

Type of study: RCT

Setting and country: prospective randomized trial in a hospital in Hawaii.

Funding and conflicts of interest:

This study was supported by a grant from The Queen Emma Research Fund,

Honolulu, Hawaii.

Conflict of interest not stated.

Condition: severe sepsis or septic shock

Domain: ICU

Ventilated: all

Inclusion criteria:

Patients 18 years or older fulfilling the criteria of severe sepsis and septic shock undergoing pulmonary artery catheter insertion.

Exclusion criteria:

Not described.

N, age, sex:

I: 39, 61±18, 62% male.

C: 30, 67±16, 57% male.

Groups were comparable at baseline.

Intervention (PtcO₂) goals:

SBP ≥ 100 mmHg

Urine output > 0.5 mL/kg/h

Lactate level normal or decreasing

OCT ≥ 40 mmHg

Baseline PtCO₂ ≥ 30 mmHg

Control (DO₂) goals:

SBP ≥ 100 mmHg

Urine output >0.5 mL/kg/h

Lactate level normal or decreasing

Age > 75:

DO₂ > 450 mL/min/m²

SVO₂ ≥ 70%

Age ≤ 75:

DO₂ > 600 mL/min/m²

SVO₂ ≥ 70%

Length of follow-up:

28 days?

Loss-to-follow-up:

None

Incomplete outcome data:

None

1. Mortality (28 days?)

I: 5/39 (13%)

C: 12/30 (40%)

P=0.02

RR (95% CI):

0.32 (0.13, 0.81)

2. ICU length of stay (days)

I: 17±14

C: 19±16

P=0.59

Mean difference (95% CI):

-2.00 (-9.22, 5.22)

3. Hospital length of stay (days)

I: 35±26

C: 43±36

P=0.31

Mean difference (95% CI):

-8.00 (-23.25, 7.28)

Yu, 2017

Type of study: RCT

Setting and country: single-center, prospective, randomized, controlled trial at Northern Jiangsu People’s Hospital, China.

Funding and conflicts of interest:

No funding reported. None of the authors declared any conflict of interest associated with this study.

Condition: septic shock

Domain: ICU

Ventilated: all

Inclusion criteria:

(1) patient had COPD-associated septic shock (consistent with the diagnostic criteria for COPD and septic);

(2) patient was treated by invasive mechanical ventilation.

Exclusion criteria:

Acute myocardial

infarction; severe arrhythmia, such as ventricular tachycardia within 24 h; or severe heart valve disease, such as severe tricuspid regurgitation; or patient was predicted to die within 24.

N, age, sex:

I: 34, 70±6.5, 59% male.

C: 37, 71±5.7, 57% male.

Groups were comparable at baseline.

Intervention goals:

GEDVI = 800 mL/m²

MAP ≥ 65 mmHg

Control goals:

CVP = 12 mmHg

MAP ≥ 65 mmHg

Length of follow-up:

90 days

Loss-to-follow-up:

3 (out of 37) patients in the control group and 1 (out of 35) in the study group were lost to follow-up.

Incomplete outcome data:

None

1. Mortality (90d)

I: 14/34 (41.5%)

C: 20/37 (54%)

P=0.30

RR (95% CI):

0.59 (0.23, 1.52)

2. ICU mortality

I: 7/34 (20.6%)

C: 10/37 (27.0%)

P>0.05

RR (95% CI):

0.76 (0.33, 1.78)

3. ICU length of stay (days)

I: 7.4±1.9

C: 11.3±2.1

P<0.05

Mean difference (95% CI):

-3.90 (-4.93, 2.97)

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Pan, 2019

yes

yes

yes

unclear

N.A.

yes

yes

Yes

unclear

Lu, 2018

yes

yes

yes

yes

N.A.

yes

yes

unclear

yes

Chen, 2017

yes

yes

yes

unclear

N.A.

yes

yes

Yes, there was no significant funnel plot asymmetry.

yes

Jiang, 2016

yes

yes

yes

yes

N.A.

yes

yes

The number of included studies was too small to perform publication bias examination.

unclear

Coccolini, 2016

yes

yes

yes

yes

N.A.

yes

yes

Significant publication biases were not recognized as shown by the symmetry of the funnel plots.

unclear

Angus, 2015

yes

yes

yes

yes

N.A.

yes

yes

Formal assessment could not be performed due to the small number of included studies..

unclear

Simpson, 2016

yes

yes

no

no

N.A.

yes

yes

unclear

unclear

Study reference

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome accessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Asfar, 2014

Randomization was performed with the use of a computer-generated assignment sequence in a centralized, blinded fashion and was stratified according to whether patients had chronic hypertension

unlikely

unlikely

likely

unlikely

Unlikely, registered trial

unlikely

unlikely

Chen, 2015

Patients were randomized to either standard (control)

therapy or TFM therapy

unlikely

unlikely

unlikely

unlikely

Unlikely, registered trial

unlikely

unlikely

Garg, 2016

Randomization was done by envelope method.

unlikely

unlikely

unlikely

unlikely

unclear

unlikely

unlikely

Kuan 2016

Blocked randomization, with randomly permutated block sizes of 4 and 6, was performed by investigators or research coordinators at the site through a Web randomization system at the Singapore Clinical Research Institute, which was not involved in patient enrollment and assessment. Before patient enrollment, a randomization list was generated with a validated SAS program (SAS Institute, Inc., Cary, NC) and then uploaded to the randomization system.

unlikely

unlikely

Unlikely, clinicians in the ward and ICU were blinded to the patients’ enrollment in either group.

unlikely

Unlikely, registered trial

unlikely

unlikely

Lanspa, 2018

Randomization was performed using random permuted blocks (2, 4, or 6 patients).

unlikely

unlikely

unlikely

unlikely

unclear

unlikely

unlikely

Lu, 2015

Not described

unlikely

unlikely

unlikely

unlikely

unclear

unlikely

unclear

Nardi, 2013

The computer-generated randomisation list was provided by an independent statistician. Allocation concealment was guaranteed using sealed opaque envelopes containing the treatment arm.

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Nardi, 2018

Randomisation (1:1 ratio) was stratified according to the study centre and balanced by blocks of 4 using a computerised random number generator list provided by an independent statistician. Sequentially numbered, sealed and opaque envelopes were used. Each envelope was assigned to a patient and opened only after the investigator wrote the patient’s information on it and faxed the signed inclusion sheet with the patient’s randomisation details to the coordinating centre.

unlikely

unlikely

unlikely

Unlikely, registered trial

unlikely

unlikely

unlikely

Palizas, 2009

Randomization was done by the central coordinator center.

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Richard, 2015

Patients were randomized with a computer-generated list using a 1:1 ratio. The allocation sequence was generated and concealed from the enrolling physician in sequentially numbered, opaque, and sealed envelopes, by a co-author who did not participate in the assessment of patient eligibility for the study.

unlikely

unlikely

unlikely

unlikely

Unlikely, registered trial

unlikely

unlikely

Su, 2018

Patients were divided in groups in accordance with randomization envelopes from the

central coordination.

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

Trof, 2012

Randomization was done by the sealed envelope method after meeting eligibility criteria. The randomization was stratified per center for sepsis versus. nonsepsis (no blocks were used).

unlikely

unlikely

unlikely

unlikely

Unlikely, registered trial

unlikely

unlikely

Yao, 2017

Not specified

unlikely

unlikely

unlikely

unlikely

unclear

unclear

unclear

Yu, 2007

Not specified

unlikely

unlikely

unlikely

unlikely

unclear

unlikely

unlikely

Yu, 2017

Patients were randomly assigned to study/control group using a random number table.

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely

unlikely