Efficacy and Safety of A Phospholipid Emulsion (GR270773) in Gram-negative Severe Sepsis: Results of A Phase II Multicenter, Randomized, Placebo-controlled, Dose-finding clinical trial
Adhikari P, Ala-Kokko T, Albert M, Anandaciva S, Angus DC, Antoniazzi P, Aslanian P, Baker AM, Bakker J, Baltopoulos G, Barie P, Barreto ML, Bassaris H, Bedos JP, Bellomo R, Beloborodova N, Belzberg H, Bishop G, Blejman S, Boldt J, Boylan A, Brodt HR, Bush L, Caballero JM, Cahn P, Calandra T, Capdevila X, Castro MT, Catorze N, Chen M, Cheng E, Cheng G, Choi SH, Chowers M, Cohen J, Conforti A, Cook P, Costandache FM, Cunha C, Cupo MA, Davidson A, De Jongh R, Dellinger PR, Dellinger RP*, Demarini T, Demeyer I, Dhainaut JF, Dicipinigaitis P, Digiovine B, Dos Santos C, Dubois MJ, Ducher A, Dugernier T, Durham R, Eaton S, El Solh A, Esteban A, Farina O, Fedossov V, Fenwick J, Finfer S, Fletcher E, Forycki F, Fraiz J, François B, Frei U, Freiberg H, French C, Friedman B, Fritz HG, Gårdlund B, Garrard C, Garrioch M, Gelfand B, Gerritsen RT, Gervich D, Giamarellos-Bourboulis E, Gil CL, Gissot V, Goldberg P, Graham N, Grimard D, Gründling M, Guzzi L, Hagberg L, Hall R, Harless K, Hata S, Heiselman D, Henderson S, Herridge M, Holzappel L, Hooper J, Horiuchi T, Hovilehto S, Hynninen M, Imm A, Intal H, Inzunza RA, Joannidis M, Kalambe B, Kalenk A, Kamarulzaman A, Kapila A, Kapravelos N, Karabinis A, Karlsson S, Karwa M, Kasal E, Keenan S, Kelly M, Kim WJ, Kivistik U, Klett I, Kljucar S, Klöss T, Kon E, Kothari V, Kozlov S, Kremzar B, Kujath P, Kumar A, Kutsogiannis D, Laine H, Larsen R, Laru-Sompa R, Laterre PF, Laupland K, Law WL, LeDoux E, Lefrant JY, Link A, Lipid Infusion and Patient Outcomes in Sepsis (LIPOS) Investigators, Liu YC, Locay H, Lucasti C, Machill K, Mallick A, Manasia A, Manuel JL, Margolis B, Markewitz B, Martin C, Martynenko T, Mascaró BS, Maskin B, McArthur C, McDermott S, McIntyre L, Meier-Hellmann A, Mertzlufft F, Miranda I, Morrison L, Motsch J, Müller T, Muzlovic I, Nikiforov Y, Nolan J, Nöldge-Schomburg G, Norambuena MM, Nul D, Oeyen S, Offenstadt G, Ogorodova L, Olthoff D, Opal S, Pai V, Papuga V, Parry M, Parviainen I, Pastores S, Pearle J, Peckelsen C, Permpikul C, Piche A, Piepenbrock S, Poirier G, Polderman KH, Potasman I, Pothirat C, Pullman J, Putensen C, Quaranta A, Quintel M, Ragaller M, Rahman MN, Raine R, Ramesh M, Raz R, Reinhart K, Remec T, Richards G, Rogers S, Romero E, Roozendaal FW, Rosolski T, Ruano M, Ruokonen E, Russell JA, Saarinen K, San Juan J, Sarapuu S, Sathe P, Saulters R, Scholz J, Shlyapnikov S, Siever J, Silva E, Simpson S, Sittipunt C, Skrobik Y, Song JH, Soukup J, Spapen H, Speer JF, Spiss CK, Spronk PE, Steingrub J, Svoboda P, Swilley J, Sy A, Tenhunen J, Tillis W, Tobin E, Tomayko JF, Torrabadella P, Tremblay L, Trottier S, Tsai YH, Tural A., Turner J, Van Heerden P, Vicari R, Vierra J, Vincent JL, Vladimir V, Vlasova N, Waldon BG, Walger P, Wang JH, Webster N, Weinstein G, Wenstone R, Williams A, Wilmer A, Wong A, Wong G, Wood G, Yang PC, Yip WC, Zanten AR, Ziegler D, Zirngibl H, Zubareva NCooper University Hospital and University Medicine Dentistry New Jersey (PD), Camden, NJ, USA. [email protected]
บทคัดย่อ
Objective: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. Design: A three-arm, randomized, blinded, placebo-controlled trial. Setting: Conducted at 235 centers worldwide between September 2004 and April 2006. Patients: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. Measurement and main results: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. Conclusions: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.
ที่มา
Critical Care Medicine ปี 2552, November
ปีที่: 37 ฉบับที่ 11 หน้า 2929-2938
