A living systematic review

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Clinical summary: This meta-analysis suggests that the clinical intervention is effective in trials that have a high control rate mortality (Over 35%); Accross all trials, the intervention is not effective and is inferior to lactate/CVP monitoring. Heterogeneity or results was moderate. The heterogeneity was 'minimal' after the rate of outcomes among controls and the type of controls were added to the meta-regression (see meta-regression below - residual I2 = 0%; 95% CI: 0% - 76%). Accordingly, the three most recent trials both had less than 30% mortality in the control group, and the intervention did not reduce mortality. The quality of evidence supporting benefit in trials with high mortality is low due to all trials being unblinded and the benefit being in a small number of subjects studied and an unplanned subgroup analysis. We considered randomized controlled trials of early-goal directed (goals met within 6 hours and goal include ScvO2 monitoring) and additional trial(s) published subsequently. Additional interpretations may be in the references in the 'Cited by' section below.

Methods overview:   Studies were abstacted into standardized tables of , and results. This repository updates a previously published meta-analysis.(1) Newer studies included are listed in the references. Rationale for newer trials excluded may be listed at the end of the references.

Results: Details of the studies included are in the:

Below is the forest plot for the primary outcome. Additional Forest plots may be available. Image of forest plot of primary outcome

The Summary of Findings Table (SoF) from the GRADE Profile is below (source files). Image of GRADE Summary of findings table


Systematic review(s)

Most recent review(s) at time of last revision of this repository

  1. Jiang LB, Zhang M, Jiang SY, Ma YF. Early goal-directed resuscitation for patients with severe sepsis and septic shock: a meta-analysis and trial sequential analysis. Scand J Trauma Resusc Emerg Med. 2016 Mar 5;24(1):23. doi: 10.1186/s13049-016-0214-7. PMID: 26946514
  2. Yu H, Chi D, Wang S, Liu B. Effect of early goal-directed therapy on mortality in patients with severe sepsis or septic shock: a meta-analysis of randomised controlled trials. BMJ Open. 2016 Mar 1;6(3):e008330. doi: 10.1136/bmjopen-2015-008330. PMID: 26932135
  3. Chelkeba L, Ahmadi A, Abdollahi M, Najafi A, Mojtahedzadeh M. Early goal-directed therapy reduces mortality in adult patients with severe sepsis and septic shock: Systematic review and meta-analysis. Indian J Crit Care Med. 2015 Jul;19(7):401-11. doi: 10.4103/0972-5229.160281. PMID: 26180433
  4. Cai G, Tong H, Hao X, Hu C, Yan M, Chen J, Yan J. [The effects of early goal-directed therapy on mortality rate in patients with severe sepsis and septic shock: a systematic literature review and Meta-analysis]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015 Jun;27(6):439-42. doi: 10.3760/cma.j.issn.2095-4352.2015.06.005. PMID: 26049180
  5. Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E. Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis. Intern Emerg Med. 2015 PMID: 25982917
  6. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015 May 8. PMID: 25952825.
  7. Zhang L, Zhu G, Han L, Fu P. Early goal-directed therapy in the management of severe sepsis or septic shock in adults: a meta-analysis of randomized controlled trials. BMC Med. 2015 Apr 3;13(1):71. PMID: 25885654
  8. Gu WJ, Wang F, Bakker J, Tang L, Liu JC. The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a meta-analysis of randomized controlled trials. Crit Care. 2014 Oct 20;18(5):570. PMID: 25327977; PMCID: PMC4232636.
  9. Wira CR, Dodge K, Sather J, Dziura J. Meta-analysis of Protocolized Goal-Directed Hemodynamic Optimization for the Management of Severe Sepsis and Septic Shock in the Emergency Department. West J Emerg Med. 2014 Feb;15(1):51-9. doi: 10.5811/westjem.2013.7.6828. PMID: 24696750; PMCID: PMC3952890.

Randomized controlled trials

New trial(s) not included in the most recent review above

  1. None

Trial(s) included

EGDT versus usual care
  1. Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015 Mar 17. [Epub ahead of print] PMID: 25776532.
  2. 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. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1. PMID: 25272316.
  3. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-93. PMID: 24635773
  4. Chen ZQ, Jin YH, Chen H, Fu WJ, Yang H, Wang RT. [Early goal-directed therapy lowers the incidence, severity and mortality of multiple organ dysfunction syndrome]. Nan Fang Yi Ke Da Xue Xue Bao. 2007 Dec;27(12):1892-5. Chinese. PMID: 18159013
  5. Early Goal-Directed Therapy Collaborative Group of Zhejiang Province. [The effect of early goal-directed therapy on treatment of critical patients with severe sepsis/septic shock: a multi-center, prospective, randomized, controlled study]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010;22(6):331-4. PMID: 20594464
  6. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-77. PMID: 11794169
EGDT versus lactate-guided therapy
  1. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-46. PMID: 20179283
  2. Wang T, Xia Y, Hao D, et al. [The significance of lactic acid in early diagnosis and goal-directed therapy of septic shock patients]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2014;26(1):51-5. Chinese. PMID: 24649525.
  3. Yu B, Tian HY, Hu ZJ, et al. [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. 2013;25(10):578-83. doi: 10.3760/cma.j.issn.2095-4352.2013.10.002. Chinese. PMID: 24119693.
  4. Tian HH, Han SS, Lv CJ, et al. [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. 2012;24(1):42-5. Chinese. PMID: 22248751

Trials undergoing review

  1. 1: Kalil AC, Johnson DW, Lisco SJ, Sun J. Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials. Crit Care Med. 2017 Apr;45(4):607-614. doi: 10.1097/CCM.0000000000002235. PMID: 28067711.
  2. Zhou X, Liu D, Su L, Yao B, Long Y, Wang X, Chai W, Cui N, Wang H, Rui X. Use of stepwise lactate kinetics-oriented hemodynamic therapy could improve the clinical outcomes of patients with sepsis-associated hyperlactatemia. Crit Care. 2017 Feb 16;21(1):33. doi: 10.1186/s13054-017-1617-1. PMID: 28202033
  3. He Z, Yang X, Yang C, Wang R, He H. [Efficacy analysis of inferior vena cava variability combined with difference of central venous-to-arterial partial pressure of carbon dioxide on guiding fluid resuscitation in patients with septic shock]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Jan;34(1):18-22. Chinese. doi: 10.3760/cma.j.cn121430-20210621-00918. PMID: 35307055.
  4. Chen H, Xu J, Wang X, Wang Y, Tong F. Early Lactate-Guided Resuscitation of Elderly Septic Patients. J Intensive Care Med. 2022 May;37(5):686-692. doi: 10.1177/08850666211023347. Epub 2021 Jun 29. PMID: 34184576.

Trials excluded - selected list of important trials

  1. Trial was terminated early: Andrews B, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Bernard GR. Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia. Crit Care Med. 2014 Nov;42(11):2315-24. doi: 10.1097/CCM.0000000000000541. PMID: 25072757; PMCID: PMC4199893.
  2. Goals were not required within 6 hours: Wang XZ, Lü CJ, Gao FQ, Li XH, Yan WF, Ning FY. [Efficacy of goal-directed therapy in the treatment of septic shock]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2006;18(11):661-4. PMID: 17092415
  3. Not randomized: He ZY, Gao Y, Wang XR, Hang YN. [Clinical evaluation of execution of early goal directed therapy in septic shock]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2007;19(1):14-6. PMID: 17207356
  4. Could not isolate results for patients with sepsis: Chen ZQ, Jin YH, Chen H, Fu WJ, Yang H, Wang RT. [Early goal-directed therapy lowers the incidence, severity and mortality of multiple organ dysfunction syndrome]. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27(12):1892-5. PMID: 18159013.
  5. Did not include goals for ScvO2: Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP. A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial. Shock. 2006;26(6):551-7. PMID: 17117128.
  6. Did not include goals for ScvO2: Tuchschmidt J, Fried J, Astiz M, Rackow E. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest. 1992;102(1):216-20. PMID: 1623756.

Funding for this review

  1. None.

Cited by

This repository is cited by:

  1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6. [Epub ahead of print] PubMed PMID: 28101605
  2. Simpson SQ, Gaines M, Hussein Y, Badgett RG. Early goal-directed therapy for severe sepsis and septic shock: A living systematic review. J Crit Care. 2016 Dec;36:43-48. PMID: 27546746
  3. WikiDoc contributors. Goal-directed therapy. WikiDoc. Fef 24, 2015. Available at: http://www.wikidoc.org/index.php/Goal-directed_therapy. Accessed February 24, 2015.