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N Engl J Med. 2017 Jun 8;376(23):2223-2234. doi: 10.1056/NEJMoa1701380. Epub 2017 Mar 21.

Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.

Collaborators (454)

Eaton TL, Keener C, Landis K, Stapleton DK, Weissfeld LA, Willochell M, Wofford KA, Kulstad E, Watts H, Venkat A, Hou PC, Massaro A, Parmar S, Limkakeng AT Jr, Brewer K, Delbridge TR, Mainhart A, Chawla LS, Miner JR, Allen TL, Grissom CK, Swadron S, Conrad SA, Carlson R, LoVecchio F, Bajwa EK, Filbin MR, Parry BA, Ellender TJ, Sama AE, Fine J, Nafeei S, Terndrup T, Wojnar M, Pearl RG, Wilber ST, Sinert R, Orban DJ, Wilson JW, Ufberg JW, Albertson T, Panacek EA, Parekh S, Gunn SR, Rittenberger JS, Wadas RJ, Edwards AR, Kelly M, Wang HE, Holmes TM, McCurdy MT, Weinert C, Harris ES, Self WH, Dubinski D, Phillips CA, Migues RM, Cameron PA, Holdgate A, Webb SA, Williams P, Cooper DJ, Cross A, Gomersall C, Graham C, Jacobs I, Johanson S, Jones P, Kruger P, McArthur C, Myburgh J, Nichol A, Pettilä V, Rajbhandari D, Williams A, Williams J, Bives G, Jovanovska A, Lam L, Little L, Newby L, Bennett V, Board J, McCracken P, McGloughlin S, Nanjayya V, Teo A, Hill E, O’Brien E, Sawtell F, Schimanski K, Wilson D, Bolch S, Eastwood G, Kerr F, Peak L, Young H, Edington J, Fletcher J, Smith J, Ghelani D, Nand K, Sara T, Flemming D, Grummisch M, Purdue A, Fulton E, Grove K, Harney A, Milburn K, Millar R, Mitchell I, Rodgers H, Scanlon S, Coles T, Connor H, Dennett J, Van Berkel A, Barrington S, Henderson S, Mehrtens J, Dryburgh J, Tankel A, Braitberg G, O’Bree B, Shepherd K, Vij S, Allsop S, Haji D, Haji K, Vuat J, Bone A, Elderkin T, Orford N, Ragg M, Kelly S, Stewart D, Woodward N, Harjola VP, Okkonen M, Sutinen S, Wilkman E, Fratzia J, Halkhoree J, Treloar S, Ryan K, Sandford T, Walsham J, Jenkins C, Williamson D, Burrows J, Hawkins D, Tang C, Dimakis A, Micallef S, Parr M, White H, Morrison L, Sosnowski K, Ramadoss R, Soar N, Wood J, Franks M, Hogan C, Song R, Tilsley A, Rainsford D, Wells R, Dowling J, Galt P, Lamac T, Lightfoot D, Walker C, Braid K, DeVillecourt T, Tan HS, Seppelt I, Chang LF, Cheung WS, Fok SK, Lam PK, Lam SM, So HM, Yan WW, Altea A, Lancashire B, Gomersall CD, Graham CA, Leung P, Arora S, Bass F, Shehabi Y, Isoardi J, Isoardi K, Powrie D, Lawrence S, Ankor A, Chester L, Davies M, O’Connor S, Poole A, Soulsby T, Sundararajan K, Greenslade JH, MacIsaac C, Gorman K, Jordan A, Moore L, Ankers S, Bird S, Fogg T, Hickson E, Jewell T, Kyneur K, O’Connor A, Townsend J, Yarad E, Brown S, Chamberlain J, Cooper J, Jenkinson E, McDonald E, Webb S, Buhr H, Coakley J, Cowell J, Hutch D, Gattas D, Keir M, Rees C, Baker S, Roberts B, Farone E, Holmes J, Santamaria J, Winter C, Finckh A, Knowles S, McCabe J, Nair P, Reynolds C, Ahmed B, Barton D, Meaney E, Harris R, Shields L, Thomas K, Karlsson S, Kuitunen A, Kukkurainen A, Tenhunen J, Varila S, Ryan N, Trethewy C, Crosdale J, Smith JC, Vellaichamy M, Furyk J, Gordon G, Jones L, Senthuran S, Bates S, Butler J, French C, Tippett A, Kelly J, Kwans J, Murphy M, O’Flynn D, Kurenda C, Otto T, Raniga V, Ho HF, Leung A, Wu H, Bell D, Bion J, Hodgetts T, Young D, Harvey S, Jahan R, Osborn T, Power S, Tan J, Corlett S, Muskett H, Scott R, Ahmed V, Boyle A, Scott-Donkin A, Black H, Smalley C, Jacob R, Wooten A, Humphrey J, Pearson SA, Griffiths J, Subramanyam D, Niblett D, Krishnanankutty S, Gao-Smith F, Melody T, Couper K, Nichani R, Brennan E, Tucker S, Benger J, Edwards J, Pollock K, Arawwawala D, Hieatt A, McNeela F, Weldring T, Carungcong J, MacNaughton P, McMillan H, Tantam K, Doyle T, Moreton S, Jones S, Kendall J, Worner R, Gilbertson A, Borland C, Boys S, Ranjan S, Smith I, Smith N, Mendham V, Smith P, Farras-Araya R, Vallance D, Watt P, Raymode P, Hollos L, Hopkins P, Riozzi P, Couper H, Helyar S, Thompson J, Hales D, Essat Z, Andreou P, Gilby S, Chilton P, Miller R, Butler J, Jefferies A, Clark R, Sanders G, Pinto N, Plowright C, Innes R, Bayford D, Richards P, Gopal S, Pooni JS, Spencer H, Napier J, Warrington E, Kevern L, Hunt J, Barrett C, Sykes E, Connelly K, Yates B, Carle C, Croft T, Jenkins N, Reschreiter H, Camsooksai J, Barcraft-Barnes H, Snelson C, Bergin C, Keats F, Linnett V, Ritzema J, Christian S, Harvey D, Miller P, Woodford C, Bolland A, Keating L, Mossop D, Jones C, Martin D, Willett E, Swallow P, McBride S, Ijaz A, Datta J, Craig J, Owen T, Williams A, McMullan S, Baldwin J, Zuleika M, Carvalho P, Agranoff D, Ingoldby F, Ortiz-Ruiz De Gordoa L, Ridley C, Clement I, Higham C, Martin B, Clayton K, Chadwick J, Frey C, Miller D, Laverick P, Iftikhar K, Higgins D, Katsande V, Chikungwa M, Jackson C, Watters M, Liddiard P, Gannon K, Howard-Griffin R, Bell S, Blaylock H, Gonzalez I, Cirstea E, Bonner S, Moondi P, Wong K, Carter J, Hartley S, Crossingham I, Hinchcliffe J, Phoenix L, Harris T, Pott J, Bellhouse G, Mercer M, Mercer P, Robinson H, Brealey D, Ryu J, Becardes G, Morris AM, Poulson M, Barnett L, Massey I, Skene I, Nee P, Dowling S, McCairn A, Duckitt R, Venn R, Margalef J, Redman J, Milner H, Ma S.

Author information

1
Intensive Care National Audit and Research Centre, London, United Kingdom
2
University of Pittsburgh School of Medicine, Pittsburgh
3
Monash University, Melbourne, VIC, Australia
4
University of Leicester, Leicester, United Kingdom
5
University of Sydney, Sydney, Australia
6
London School of Hygiene and Tropical Medicine, London, United Kingdom
7
University of Adelaide, Adelaide, SA, Australia
8
Queen Elizabeth Hospital, Adelaide, SA, Australia
9
Eli Lilly, Indianapolis
10
University of Queensland, Brisbane, Australia
11
University College London, London, United Kingdom

Abstract

BACKGROUND:

After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT.

METHODS:

We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics.

RESULTS:

We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation.

CONCLUSIONS:

In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).

PMID:
28320242
DOI:
10.1056/NEJMoa1701380
[Indexed for MEDLINE]
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