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8. Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support–free days in patients hospitalized with COVID-19

Author

Writing Committee for the REMAP-CAP Investigators, Lawler, PR, Derde, LPG, Van de Veerdonk, FL, McVerry, BJ, Huang, DT, Berry, LR, Lorenzi, E, Van Kimmenade, R, Gommans, F, Vaduganathan, M, Leaf, DE, Baron, RM, Kim, EY, Frankfurter, C, Epelman, S, Kwan, Y, Grieve, R, O'Neill, S, Sadique, Z, Puskarich, M, Marshall, JC, Higgins, AM, Mouncey, PR, Rowan, KM, Al-Beidh, F, Annane, D, Arabi, YM, Au, C, Beane, A, Van Bentum-Puijk, W, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Burrell, A, Buzgau, A, Buxton, M, Cecconi, M, Cheng, AC, Cove, M, Detry, MA, Estcourt, LJ, Ezekowitz, J, Fitzgerald, M, Gattas, D, Godoy, LC, Goossens, H, Haniffa, R, Harrison, DA, Hills, T, Horvat, CM, Ichihara, N, Lamontagne, F, Linstrum, KM, McAuley, DF, McGlothlin, A, McGuinness, SP, McQuilten, Z, Murthy, S, Nichol, AD, Owen, DRJ, Parke, RL, Parker, JC, Pollock, KM, Reyes, LF, Saito, H, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Singh, V, Turgeon, AF, Turner, AM, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, Berry, S, Gordon, AC, McArthur, CJ, and Webb, SA

Abstract

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Published
2023

9. Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Author

Florescu, S, Stanciu, D, Zaharia, M, Kosa, A, Codreanu, D, Kidwai, A, Masood, S, Kaye, C, Coutts, A, MacKay, L, Summers, C, Polgarova, P, Farahi, N, Fox, E, McWilliam, S, Hawcutt, D, Rad, L, O’Malley, L, Whitbread, J, Jones, D, Dore, R, Saunderson, P, Kelsall, O, Cowley, N, Wild, L, Thrush, J, Wood, H, Austin, K, Bélteczki, J, Magyar, I, Fazekas, Á, Kovács, S, Szőke, V, Donnelly, A, Kelly, M, Smyth, N, O’Kane, S, McClintock, D, Warnock, M, Campbell, R, McCallion, E, Azaiz, A, Charron, C, Godement, M, Geri, G, Vieillard-Baron, A, Johnson, P, McKenna, S, Hanley, J, Currie, A, Allen, B, McGoldrick, C, McMaster, M, Mani, A, Mathew, M, Kandeepan, R, Vignesh, C, TV, B, Ramakrishnan, N, James, A, Elvira, E, Jayakumar, D, Pratheema, R, Babu, S, Ebenezer, R, Krishnaoorthy, S, Ranganathan, L, Ganesan, M, Shree, M, Guilder, E, Butler, M, Cowdrey, K-A, Robertson, M, Ali, F, McMahon, E, Duffy, E, Chen, Y, Simmonds, C, McConnochie, R, O’Connor, C, El-Khawas, K, Richardson, A, Hill, D, Commons, R, Abdelkharim, H, Saxena, M, Muteithia, M, Dobell-Brown, K, Jha, R, Kalogirou, M, Ellis, C, Krishnamurthy, V, O’Connor, A, Thurairatnam, S, Mukherjee, D, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Maloney, G, Kittridge, L, Solesbury, A, Ramos, A, Collins, D, Brickell, K, Reid, L, Smyth, M, Breen, P, Spain, S, Curley, G, McEvoy, N, Geoghegan, P, Clarke, J, Silversides, J, McGuigan, P, Ward, K, O’Neill, A, Finn, S, Wright, C, Green, J, Collins, É, Knott, C, Smith, J, Boschert, C, Slieker, K, Ewalds, E, Sanders, A, Wittenberg, W, Geurts, H, Poojara, L, Sara, T, Nand, K, Reeve, B, Dechert, W, Phillips, B, Oritz-Ruiz de Gordoa, L, Affleck, J, Shaikh, A, Murray, A, Ramanan, M, Frakking, T, Pinnell, J, Robinson, M, Gledhill, L, Wood, T, Sanghavi, R, Bhonagiri, D, Ford, M, Parikh, HG, Avard, B, Nourse, M, McDonald, B, Edmunds, N, Hoiting, O, Peters, M, Rengers, E, Evers, M, Prinssen, A, Morgan, M, Cole, J, Hill, H, Davies, M, Williams, A, Thomas, E, Davies, R, Wise, M, Grimm, P, Soukup, J, Wetzold, R, Löbel, M, Starke, L, Lellouche, F, Lizotte, P, Declerq, P, Antoine, M, Stephanie, G, Jean-Pierre, E, François, B, Marion, B, Philippe, R, Pourcine, F, Monchi, M, Luis, D, Mercier, R, Sagnier, A, Verrier, N, Caplin, C, Richecoeu, J, Combaux, D, Siami, S, Aparicio, C, Vautier, S, Jeblaoui, A, Lemaire-Brunel, D, D'Aragon, F, Carbonneau, E, Leblond, J, Plantefeve, G, Leparco, C, Contou, D, Fartoukh, M, Courtin, L, Labbe, V, Voiriot, G, Salhi, S, Chassé, M, Carrier, F, Boumahni, D, Benettaib, F, Ghamraoui, A, Sement, A, Gachet, A, Hanisch, A, Haffiane, A, Boivin, A-H, Barreau, A, Guerineau, E, Poupblanc, S, Egreteau, P, Lefevre, M, Bocher, S, Le Loup, G, Le Guen, L, Carn, V, Bertel, M, Antcliffe, D, Templeton, M, Rojo, R, Coghlan, P, Smee, J, Barker, G, Finn, A, Kreb, G, Hoff, U, Hinrichs, C, Nee, J, Mackay, E, Cort, J, Whileman, A, Spencer, T, Spittle, N, Beavis, S, Padmakumar, A, Dale, K, Hawes, J, Moakes, E, Gascoyne, R, Pritchard, K, Stevenson, L, Cooke, J, Nemeth-Roszpopa, K, Gauli, B, Bastola, S, Muller, G, Nay, M-A, Kamel, T, Benzekri, D, Jacquier, S, Runge, I, Mathonnet, A, Barbier, F, Bretagnol, A, Carter, J, Van Der Heyden, K, Mehrtens, J, Morris, A, Morgan, S, Burke, T, Mercier, E, Chartier, D, Salmon, C, Dequin, P-F, Garot, D, Bellemare, D, Cloutier, È, Daher, R, Costerousse, O, Boulanger, M-C, Couillard-Chénard, É, Lauzier, F, Francoeur, C, Francois, B, Gay, A, Anne-Laure, F, Ramali, M, HC, O, Ghosh, A, Osagie, R, Arachchige, M, Hartley, M, Cheung, W, Wong, H, Seigne, P, Eustace, J, O'Callaghan, A-M, O'Brien, F, Bamford, P, Reid, A, Cawley, K, Faulkner, M, Pickering, C, Raj, A, Tsinaslanidis, G, Khade, R, Agha, G, Sekiwala, R, Smith, T, Brewer, C, Gregory, J, Limb, J, Cowton, A, O’Brien, J, Postlethwaite, K, Malakouti, S, Music, E, Ricketts, D, King, A, Clermont, G, Bart, R, Mayr, F, Schoenling, A, Andreae, M, Shetty, V, Brant, E, Malley, B, Donadee, C, Sackrowitz, R, Weissman, A, Yealy, D, Barton, D, Talia, N, Nikitas, N, Wells, C, Lankester, L, McMillan, H, Van den Oever, H, Kruisdijk-Gerritsen, A, Haidar, G, Bain, W, Barbash, I, Fitzpatrick, M, Franz, C, Kitsios, G, Moghbeli, K, Rosborough, B, Shah, F, Suber, T, Pulletz, M, Williams, P, Birch, J, Wiseman, S, Horton, S, Alegria, A, Turki, S, Elsefi, T, Crisp, N, Allen, L, Truman, N, Smith, M, Chukkambotla, S, Goddard, W, Duberley, S, Khan, M, Kazi, A, Simpson, J, Duke, G, Chan, P, Carter, B, Hunter, S, Voigt, I, Schueler, R, Blank, E, Hüning, V, Steffen, M, Goralski, P, Litton, E, Regli, A, Pellicano, S, Palermo, A, Eroglu, E, Bihari, S, Laver, RD, Jin, X, Brown, J, McIntyre, J, French, C, Bates, S, Towns, M, Yang, Y, McGain, F, McCullagh, I, Cairns, T, Hanson, H, Patel, B, Clement, I, Evetts, G, Touma, O, Holland, S, Hodge, C, Taylor, H, Alderman, M, Barnes, N, Da Rocha, J, Smith, C, Brooks, N, Weerasinghe, T, Sinclair, J-A, Abusamra, Y, Doherty, R, Cudlipp, J, Singh, R, Yu, H, Daebis, A, Ng, C, Kendrick, S, Saran, A, Makky, A, Greener, D, Rowe-Leete, L, Edwards, A, Bland, Y, Dolman, R, Foster, T, Laffey, J, McNicholas, B, Scully, M, Casey, S, Kernan, M, Brennan, A, Rangan, R, Tully, R, Corbett, S, McCarthy, A, Duffy, O, Burke, D, Linnett, V, Sanderson, A, Ritzema, J, Wild, H, Lucas, R, Marriott, Y, Andric, Z, Cviljevic, S, Br, R, Zapalac, M, Mirković, G, Khare, D, Pinder, M, Gopinath, A, Kannan, T, Dean, S, Vanmali, P, Depuydt, P, De Waele, J, De Bus, L, Fierens, J, Bracke, S, Vermassen, J, Vermeiren, D, Pugh, R, Lean, R, Qiu, X, Scanlan, J, Evans, A, Davies, G, Lewis, J, Plesnikova, Y, Khoud, A, Coetzee, S, Puxty, K, Cathcart, S, Rimmer, D, Bagot, C, Scott, K, Martin, L, Yusuff, H, Isgro, G, Brightling, C, Bourne, M, Craner, M, Boyles, R, Alexander, B, Roberts, T, Nelli, A, Rosenstein-Sisson, R, Speyer, R, Pech, Y, McCullough, J, Tallott, M, Vazquez-Grande, G, Marten, N, Liu, T, Siddiqui, A, Khanal, S, Amatya, S, Szakmany, T, Cherian, S, Williams, G, James, C, Waters, A, Prout, R, Stedman, R, Davies, L, Pegler, S, Kyeremeh, L, Moorhouse, L, Arbane, G, Marotti, M, Bociek, A, Campos, S, Van Nieuwkoop, K, Ottens, T, Visser, Y, Van den Berg, L, Van der Kraan-Donker, A, Brett, S, Arias, S, Hall, R, Paneru, H, Koirala, S, Paudel, P, Wilson, M, Vaara, S, Pettilä, L, Heinonen, J, Pettilä, V, Jain, S, Gupta, A, Holbrook, C, Antoine, P, Meziani, F, Allam, H, Cattelan, J, Clere-Jehl, R, Helms, J, Kummerlen, C, Merdji, H, Monnier, A, Rahmani, H, Studer, A, Schneider, F, Castelain, V, Morel, G, L’Hotellier, S, Ochin, E, Vanjak, C, Rouge, P, Bendjemar, L, Albert, M, Serri, K, Cavayas, A, Duplaix, M, Williams, V, Catorze, NJTADS, Pereira, TNAL, Ferreira, RMC, Bastos, JMPS, Batista, TMO, Badie, J, Berdaguer, F, Malfroy, S, Mezher, C, Bourgoin, C, Moneger, G, Bouvier, E, Muñoz-Bermúdez, R, Marin-Corral, J, Degracia, A, Gómez, F, López, M, Aceto, R, Aghemo, A, Badalamenti, S, Brunetta, E, Cecconi, M, Ciccarelli, M, Constantini, E, Greco, M, Folci, M, Selmi, C, Voza, A, Henning, J, Bonner, S, Hugill, K, Cirstea, E, Wilkinson, D, Jones, J, Altomy, M, Karlikowski, M, Sutherland, H, Wilhelmsen, E, Woods, J, North, J, Pletz, M, Hagel, S, Ankert, J, Kolanos, S, Bloos, F, Simons, K, Van Zuylen, T, Bouman, A, Kumar, N, Panwar, R, Poulter, A-L, Sunkara, K, Szigligeti, G, Leszkoven, J, Rochwerg, B, Karachi, T, Oczkowski, S, Centofanti, J, Millen, T, Sundaran, D, Hollos, L, Turns, M, Walsh, J, Al Qasim, E, Alswaidan, L, Hegazy, M, Arishi, H, Al Amri, A, AlQahtani, S, Naidu, B, Tlayjeh, H, Hussain, S, Al Enezi, F, Abdukahil, SA, Hopkins, P, Noble, H, O’Reilly, K, Mehta, R, Wong, O, Makanju, E, Rao, D, Sikondari, N, Saha, S, Corcoran, E, Pappa, E, Cockrell, M, Donegan, C, Balaie, M, Nickoleit-Bitzenberger, D, Schaaf, B, Meermeier, W, Prebeg, K, Azzaui, H, Hower, M, Brieger, K-G, Elender, C, Sabelhaus, T, Riepe, A, Akamp, C, Kremling, J, Klein, D, Landsiedel-Mechenbier, E, Laha, S, Verlander, M, Jha, A, Megarbane, B, Voicu, S, Deye, N, Malissin, I, Sutterlin, L, Mrad, A, Lehalleur, A, Naim, G, Nguyen, P, Ekhérian, J-M, Boué, Y, Sidéris, G, Vodovar, D, Guérin, E, Grant, C, Brain, M, Mineall, S, Paramasivam, E, Wilby, E, Ogg, B, Howcroft, C, Aspinwall, A, Charlton, S, Gould, R, Mistry, D, Awan, S, Bedford, C, Carr-Wilkinson, J, Hall, A, Gardiner-Hill, C, Maloney, C, Brunskill, N, Watchorn, O, Hardy, C, Qureshi, H, Flint, N, Nicholson, S, Southin, S, Ghattaoraya, A, Harding, D, O’Halloran, S, Collins, A, Smith, E, Trues, E, Borgatta, B, Turner-Bone, I, Reddy, A, Wilding, L, Wilson, C, Surti, Z, Aneman, A, Miller, J, White, H, Estensen, K, Morrison, L, Sutton, J, Cooper, M, Warnapura, L, Agno, R, Sathianathan, P, Shaw, D, Ijaz, N, Spong, A, Sabaretnam, S, Burns, D, Lang, E, Tate, M, Fischer, R, Biradar, V, Soar, N, Golden, D, Davey, M, Seaman, R, Osborne, A, Bannard-Smith, J, Clark, R, Birchall, K, Henry, J, Pomeroy, F, Quayle, R, Wylie, K, Sukuraman, A, John, M, Sibin, S, Leditschke, A, Finnis, M, Jongebloed, K, Khwaja, K, Campisi, J, Van Vonderen, M, Pietersma, M, Vrolijk, L, Kampschreur, L, Van Gulik, L, Makowski, A, Misztal, B, Haider, S, Liao, A, Squires, R, Oborska, A, Kayani, A, Kalchko-Veyssal, S, Prabakaran, R, Hadebe, B, KalchkoVeyssal, S, Williams, T, Song, R, Morpeth, S, Lai, V, Habraken, H, Stewart, R, Mwaura, E, Mew, L, Wren, L, Willams, F, Sutherland, S-B, Rebello, R, Shehabi, Y, Al-Bassam, W, Hulley, A, Kadam, U, Sathianathan, K, Innes, R, Doble, P, Graham, L, Shovelton, C, Dean, T, Salahuddin, N, Aryal, D, Koirala, K, Rai, N, Luitel, S, Seppelt, I, Whitehead, C, Lowrey, J, Gresham, R, Masters, K, Hamlyn, V, Hawkins, N, Roynon-Reed, A, Cutler, S, Lewis, S, Lazaro, J, Newman, T, Aravindan, L, Asghar, A, Bartholomew, J, Bayne, M, Beddows, S, Birch, C, Brend, M, Byrne, R, Campbell, D, Campbell, H, Chambers, E, Clinton, A, Collins, J, Crawshaw, S, Dawson, LA, Donaldson, K, Drake, C, Dyas, S, Ellis, Y, Gilmour, K, Goodwin, J, Halden, S, Hall, AS, Hanson, J, Harper, H, Harrison, S, Hayes, A, Hodgson, H, Hurford, S-A, Jackson, S, Levett, C, Lock, S, Lockett, T, Logan, M, Lomme, K, Luo, J, Marsh, E, Mguni, N, Monaghan, H, Murphy, S, Muzengi, N, Naz, M, O'Kell, E, Oliver, A, O'Reilly, J, Pearson, K, Porter, D, Potter, A, Rook, C, Rounds, C, Sheffield, J, Shirley, K, Siewersk, C, Skinner, T, Speight, H, Sutu, M, Unsworth, A, Van’t Hoff, W, Walker, S, Williams, H, Williamson, D, Williamson, JD, Duan, E, Tsang, J, Patterson, L, Austin, P, Chapman, S, Cabrelli, L, Fletcher, S, Nortje, J, Fottrell-Gould, D, Randell, G, Stammers, K, Healey, G, Pinto, M, Borrill, Z, Duncan, T, Ustianowski, A, Uriel, A, Eltayeb, A, Alfonso, J, Hey, S, Shaw, J, Fox, C, Lindergard, G, Charles, B, Blackledge, B, Connolly, K, Harris, J, Cuesta, J, Xavier, K, Purohit, D, Elhassan, M, Haldeos, A, Vincent, R, Abdelrazik, M, Jenkins, S, Ganesan, A, Kumar, R, Carter, D, Bakthavatsalam, D, Frater, A, Saleem, M, Everitt, R, Hacking, D, Zaman, M, Elmahi, E, Jones, A, Hall, K, Phillips, M, Terrill, L, Mills, G, Raithatha, A, Bauchmuller, K, Ryalls, K, Harrington, K, Bowler, H, Sall, J, Bourne, R, Gross, J, Massey, N, Adebambo, O, Long, M, Tony, K, Juffermans, N, Koopmans, M, Dujardin, R, Alderink, B, Rowland, M, Hutton, P, Bashyal, A, Davidson, N, Hird, C, Chhablani, M, Phalod, G, Kirkby, A, Archer, S, Netherton, K, Reschreiter, H, Camsooksai, J, Patch, S, Humphrey, C, Flynn, G, Harrington, C, Kruger, P, Walsham, J, Meyer, J, Harward, M, Jones, C, Sathe, S, Roche, L, Davies, E, Skinner, D, Gaylard, J, Newman, J, Pogson, D, Rose, S, Daly, Z, Brimfield, L, Nown, A, Parekh, D, Bergin, C, Bates, M, McGhee, C, Lynch, D, Bhandal, K, Tsakiridou, K, Bamford, A, Cooper, L, Whitehouse, T, Veenith, T, Forster, E, O'Connell, M, Sim, M, Hay, S, Henderson, S, Nygren, M, Valentine, E, Katary, A, Bell, G, Wilcox, L, Mataliotakis, M, Smith, P, Ali, M, Isguzar, A, Phull, M-K, Zaidi, A, Pogreban, T, Rosaroso, L, Harvey, D, Lowe, B, Meredith, M, Ryan, L, Schouten, J, Pickkers, P, Roovers, N, Klop-Riehl, M, Van der Eng, H, Sloots-Cuppen, S, Preijers, L, Van Oosten, N, Moine, P, Heming, N, Maxime, V, Bossard, I, Nicholier, T, Clair, B, Orlikowski, D, Bounab, R, Abdeladim, L, Baker, S, Duroux, M, Ratcliffe, M, Sy, E, Mailman, J, Lee, S, Gupta, C, Kassir, S, López, R, Rodríguez-Gómez, J, Cárcel, S, Carmona, R, De la Fuente, C, Rodriguez, M, Jan Hassing, R, Greven, F, Huijbens, D, Roebers, L, Verheij, H, Miles, H, Attokaran, A, Buehner, U, Williams, E, Chapman, M, O’Connor, S, Glasby, K, Rivett, J, Brown, N, Kutsogiannis, D, Thompson, P, Rooney, K, Rodden, N, Thomson, N, McGlynn, D, Abel, L, Gemmell, L, Sundaram, R, Hornsby, J, Walden, A, Keating, L, Frise, M, Rai, S, Bartley, S, Schuster-Bruce, M, Pitts, S, Miln, R, Purandare, L, Vamplew, L, Dempster, D, Gummadi, M, Dormand, N, Wang, S, Spivey, M, Bean, S, Burt, K, Moore, L, Hammonds, F, Richards, C, Campbell, L, Smyth, K, Day, C, Zitter, L, Benyon, S, Singh, J, Lynch, C, Mikusek, J, Deacon, B, Turner, K, Baker, E, Hickey, J, Champanerkar, S, Aitken, L, LewisProsser, L, Ahmad, N, Wiles, M, Willson, J, Grecu, I, Martin, J, Wrey Brown, C, Arias, A-M, Bevan, E, Westlake, S, Craven, T, Hope, D, Singleton, J, Clark, S, McCulloch, C, Biddie, S, Welters, I, Hamilton, D, Williams, K, Waugh, V, Mulla, S, Waite, A, Roman, J, Martinez, M, Johnston, B, Puthucheary, Z, Martin, T, Santos, F, Uddin, R, Fernandez, M, Seidu, F, Somerville, A, Pakats, M-L, Begum, S, Shahid, T, Presneill, J, Barge, D, Byrne, K, Janin, P, Yarad, E, Bass, F, Hammond, N, Vuylsteke, A, Chan, C, Victor, S, Waterson, S, McNamara, R, Boardman, M, Gattas, D, Buhr, H, Coles, J, Matsa, R, Gellamucho, M, Creagh-Brown, B, Marriot, C, Salberg, A, Zouita, L, Stone, S, Michalak, N, Donlon, S, Mtuwa, S, Mayangao, I, Verula, J, Burda, D, Harris, C, Jones, E, Bradley, P, Tarr, E, Harden, L, Piercy, C, Nolan, J, Kerslake, I, Cook, T, Simpson, T, Dalton, J, Demetriou, C, Mitchard, S, Ramos, L, White, K, Johnson, T, Headdon, W, Spencer, S, White, A, Howie, L, Reay, M, Watts, A, Traverse, E, Jennings, S, Anumakonda, V, Tuckwell, C, Harrow, K, Matthews, J, McGarry, K, Moore, V, Smith, L, Summerfield, A, Dark, P, Harvey, A, Doonan, R, McMorrow, L, Knowles, K, Pendlebury, J, Perez, J, Marsden, T, Taylor, M, Michael, A, Collis, M, Claxton, A, Habeichi, W, Horner, D, Slaughter, M, Thomas, V, Proudfoot, N, Keatley, C, Donnison, P, Casey, R, Irving, B, Matimba-Mupaya, W, Reed, C, Anthony, A, Trim, F, Cambalova, L, Robertson, D, Wilson, A, Hulme, J, Kannan, S, Kinney, F, Senya, H, Ratnam, V, Gill, M, Kirk, J, Shelton, S, Schweikert, S, Wibrow, B, Anstey, M, Rauniyar, R, Khoso, N, Asif, N, Taqdees, H, Frey, C, Scano, R, McKee, M, Murphy, P, Thomas, M, Worner, R, Faulkner, B, Gendall, E, Hayes, K, Blakemore, H, Borislavova, B, Deshpande, K, Van Haren, F, Konecny, P, Inskip, D, Tung, R, Hayes, L, Murphy, L, Neill, A, Reidy, B, O’Dwyer, M, Ryan, D, Ainscough, K, Hamilton-Davies, C, Mfuko, C, Abbass, H, Mandadapu, V, Leaver, S, Patel, K, Farnell-Ward, S, Saluzzio, R, Rawlins, S, Sicat, C, De Keulenaer, B, Ferrier, J, Fysh, E, Davda, A, Mevavala, B, Cook, D, Clarke, F, Banach, D, Fernández de Pinedo Artaraz, Z, Cabreros, L, Latham, V, Kruisselbrink, R, Brochard, L, Burns, K, Sandhu, G, Khalid, I, White, I, Croft, M, Holland, N, Pereira, R, Nair, P, Buscher, H, Reynolds, C, Newman, S, Santamaria, J, Barbazza, L, Homes, J, Smith, R, Zaki, A, Johnson, D, Garrard, H, Juhaz, V, Brown, L, Pemberton, A, Roy, A, Rostron, A, Woods, L, Cornell, S, Fowler, R, Adhikari, N, Kamra, M, Marinoff, N, Garrett, P, Murray, L, Brailsford, J, Fennessy, G, Mulder, J, Morgan, R, Pillai, S, Harford, R, Ivatt, H, Evans, D, Richards, S, Roberts, E, Bowen, J, Ainsworth, J, Kuitunen, A, Karlsson, S, Vahtera, A, Kiiski, H, Ristimäki, S, Albrett, J, Jackson, C, Kirkham, S, Tamme, K, Reinhard, V, Ellervee, A, Põldots, L, Rennit, P, Svitškar, N, Browne, T, Grimwade, K, Goodson, J, Keet, O, Callender, O, Udy, A, McCracken, P, Young, M, Board, J, Martin, E, Kasipandian, V, Patel, A, Allibone, S, Mary-Genetu, R, English, S, Watpool, I, Porteous, R, Miezitis, S, McIntyre, L, Brady, K, Vale, C, Shekar, K, Lavana, J, Parmar, D, Peake, S, Kurenda, C, Hormis, A, Walker, R, Collier, D, Kimpton, S, Oakley, S, Bhagani, S, De Neef, M, Garcia, S, Maharajh, A, Nandani, A, Dobson, J, Fernando, G, Eastgate, C, Gomez, K, Abdi, Z, Tatham, K, Jhanji, S, Black, E, Dela Rosa, A, Howle, R, Baikady, R, Drummond, A, Dearden, J, Philbin, J, Munt, S, Gopal, S, Pooni, J-S, Ganguly, S, Smallwood, A, Metherell, S, Naeem, A, Fagan, L, Ryan, E, Mariappa, V, Foulds, A, Revill, A, Bhattarai, B, De Jonge, E, Wigbers, J, Del Prado, M, Cremer, O, Mulier, J, Peters, A, Romberg, B, Schutgens, R, Troeman, D, Van Opdorp, M, Besten, H, Brakké, K, Barber, R, Hilldrith, A, Kluge, S, Nierhaus, A, Jarczak, D, Roedl, K, Kochanek, M, Rueß-Paterno, G, Mc-Kenzie, J, Eichenauer, D, Shimabukuro-Vornhagen, A, Wilcox, E, Del Sorbo, L, Abdelhady, H, Romagnuolo, T, Simpson, S, Maiden, M, Horton, M, Trickey, J, Krajinovic, V, Kutleša, M, Kotarski, V, Brohi, F, Jagannathan, V, Clark, M, Purvis, S, Wetherill, B, Brajković, A, Babel, J, Sever, H, Dragija, L, Kušan, I, Dushianthan, A, Cusack, R, De Courcy-Golder, K, Salmon, K, Burnish, R, Smith, S, Ruiz, W, Duke, Z, Johns, M, Male, M, Gladas, K, Virdee, S, Swabe, J, Tomlinson, H, Rohde, G, Grünewaldt, A, Bojunga, J, Petros, S, Kunz, K, Schütze, B, Weismann, D, Frey, A, Drayss, M, Goebeler, ME, Flor, T, Fragner, G, Wahl, N, Totzke, J, Sayehli, C, Hakak, S, Altaf, W, O'Sullivan, M, Murphy, A, Walsh, L, Rega La Valle, A, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Wyatt, R, Morgan, K, Varghese, S, Willis, J, Stratton, E, Kyle, L, Putensen, D, Drury, K, Skorko, A, Bremmer, P, Ward, G, Bassford, C, Sligl, W, Baig, N, Rewa, O, Bagshaw, S, Basile, K, Stavor, D, Burbee, D, McNamara, A, Wunderley, R, Bensen, N, Adams, P, Vita, T, Buhay, M, Scholl, D, Gilliam, M, Winters, J, Doherty, K, Berryman, E, Ghaffari, M, Marroquin, O, Quinn, K, Garrard, W, Kalchthaler, K, Beard, G, Skrtich, A, Bagavathy, K, Drapola, D, Bryan-Morris, K, Arnold, J, Reynolds, B, Hussain, M, Dunsavage, J, Saiyed, S, Hernandez, E, Goldman, J, Brown, C, Comp, S, Raczek, J, Morris, J, Vargas Jr., J, Weiss, D, Hensley, J, Kochert, E, Wnuk, C, Nemeth, C, Mowery, B, Hutchinson, C, Winters, L, McAdams, D, Walker, G, Minnier, T, Wisniewski, M, Mayak, K, McCreary, E, Bariola, R, Viehman, A, Daley, J, Lopus, A, Schmidhofer, M, Ambrosino, R, Keen, S, Toffalo, S, Stambaugh, M, Trimmer, K, Perri, R, Casali, S, Medva, R, Massar, B, Beyerl, A, Burkey, J, Keeler, S, Lowery, M, Oncea, L, Daugherty, J, Sevilla, C, Woelke, A, Dice, J, Weber, L, Roth, J, Ferringer, C, Beer, D, Fesz, J, Carpio, L, Colin, G, Zinzoni, V, Maquigneau, N, Henri-Lagarrigue, M, Pouplet, C, Reill, L, Distler, M, Maselli, A, Martynoga, R, Trask, K, Butler, A, Attwood, B, Parsons, P, Campbell, B, Smith, A, Page, V, Zhao, X, Oza, D, Abrahamson, G, Sheath, B, Young, P, Young, C, Lesona, E, Navarra, L, Cruz, R, Delaney, K, Aguilar-Dano, A, Gojanovic, M, Rhodes, J, Anderson, T, Morris, S, Nayyar, V, Bowen, D, Kong, J, Joy, J, Fuchs, R, Lambert, B, Tai, C, Thomas, A, Keen, A, Tierney, C, Omer, N, Bacon, G, Tridente, A, Shuker, K, Anders, J, Greer, S, Scott, P, Millington, A, Buchanan, P, Binnie, A, Powell, E, McMillan, A, Luk, T, Aref, N, Denmade, C, Sadera, G, Jacob, R, Hughes, D, Sterba, M, Geng, W, Digby, S, Southern, D, Reddy, H, Hulse, S, Campbell, A, Garton, M, Watkins, C, Smuts, S, Quinn, A, Simpson, B, McMillan, C, Finch, C, Hill, C, Cooper, J, Budd, J, Small, C, O’Leary, R, Collins, E, Holland, A, Alexander, P, Felton, T, Ferguson, S, Sellers, K, Ward, L, Yates, D, Birkinshaw, I, Kell, K, Scott, Z, Pearson, H, Hashmi, M, Hassan, N, Panjwani, A, Umrani, Z, Shaikh, M, Ain, Q, Kanwal, D, Van Bree, S, Bouw-Ruiter, M, Osinga, M, Van Zanten, A, McEldrew, R, Rashan, S, Singh, V, Azergui, N, Bari, S, Beltran, M, Brugman, C, Groeneveld, E, Jafarzadeh, M, Keijzer-Timmers, N, Kester, E, Koelink, M, Kwakkenbos-Craanen, M, Okundaye, C, Parker, L, Peters, S, Post, S, Rietveld, I, Scheepstra-Beukers, I, Schreuder, G, Smit, A, Brillinger, N, Markgraf, R, Eichinger, F, Doran, P, Anjum, A, Best-Lane, J, Barton, F, Miller, L, Richards-Belle, A, Saull, M, Sprinckmoller, S, Wiley, D, Darnell, R, Au, C, Lindstrum, K, Cheng, A, Forbes, A, Heritier, S, Trapani, T, Cuthbertson, B, Manoharan, V, Dondrop, A, Tolppa, T, Ehrmann, S, Hullegie, S, Povoa, P, Beasley, R, Daneman, N, McGloughlin, S, Paterson, D, Venkatesh, B, De Jong, M, Uyeki, T, Baillie, K, Netea, M, Orr, K, Patanwala, A, Tong, S, Cooper, N, Galea, J, Leavis, H, Ogungbenro, K, Patawala, A, Rademaker, E, Youngstein, T, Carrier, M, Fergusson, D, Hunt, B, Kumar, A, Laffan, M, Lother, S, Middeldorp, S, Stanworth, S, De Man, A, Masse, M-H, Abraham, J, Arnold, D, Begin, P, Charlewood, R, Chasse, M, Coyne, M, Daly, J, Gosbell, I, Harvala-Simmonds, H, MacLennan, S, McDyer, J, Menon, D, Pridee, N, Roberts, D, Thomas, H, Tinmouth, A, Triulzi, D, Walsh, T, Wood, E, Calfee, C, O’Kane, C, Shyamsundar, M, Sinha, P, Thompson, T, Young, I, Burrell, A, Ferguson, N, Hodgson, C, Orford, N, Phua, J, Baron, R, Epelman, S, Frankfurter, C, Gommans, F, Kim, E, Leaf, D, Vaduganathan, M, Van Kimmenade, R, Sanil, A, Van Beurden, M, Effelaar, E, Schotsman, J, Boyd, C, Harland, C, Shearer, A, Wren, J, Attanayaka, U, Darshana, S, Ishani, P, Udayanga, I, Higgins, AM, Berry, LR, Lorenzi, E, Murthy, S, McQuilten, Z, Mouncey, PR, Al-Beidh, F, Annane, D, Arabi, YM, Beane, A, Van Bentum-Puijk, W, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Buxton, M, Charles, WN, Cove, M, Detry, MA, Estcourt, LJ, Fagbodun, EO, Fitzgerald, M, Girard, TD, Goligher, EC, Goossens, H, Haniffa, R, Hills, T, Horvat, CM, Huang, DT, Ichihara, N, Lamontagne, F, Marshall, JC, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Neal, MD, Nichol, AD, Parke, RL, Parker, JC, Parry-Billings, K, Peters, SEC, Reyes, LF, Rowan, KM, Saito, H, Santos, MS, Saunders, CT, Serpa-Neto, A, Seymour, CW, Shankar-Hari, M, Stronach, LM, Turgeon, AF, Turner, AM, Van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Derde, LPG, Gordon, AC, Webb, SA, Lawler, PR, Comm REMAP-CAP Investigators, Apollo - University of Cambridge Repository, Intensive Care Medicine, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pittsburgh Foundation, PF, Amgen, Health Research Board, HRB: CTN 2014-012, Horizon 2020 Framework Programme, H2020: 101003589, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, Heart and Stroke Foundation of Canada, HSF, National Institute for Health and Care Research, NIHR, European Commission, EC, National Health and Medical Research Council, NHMRC: 1101719, APP194811, CS-2016-16-011, GNT2008447, RP-2015-06-18, Office of Health and Medical Research, OHMR, Health Research Council of New Zealand, HRC: 16/631, Eisai, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Université Pierre et Marie Curie, UPMC, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, Funding/Support : The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Australian Medical Research Future Fund (#APP2002132), the Health Research Council of New Zealand (#16/631), the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584) and the Canadian Institute of Health Research COVID-19 Rapid Research Funding (#447335), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Wellcome Trust Innovations Project (215522), the Minderoo Foundation, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the Translational Breast Cancer Research Consortium, the NSW Office of Health and Medical Research, Amgen, Eisai, and the Pittsburgh Foundation. Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). Dr McQuilten is funded by an NHMRC Emerging Leadership Fellowship (APP194811). Dr Gordon is funded by an NIHR Research Professorship (RP-2015-06-18) and Dr Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011). Dr Turgeon is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Dr Lawler is supported by a career award from the Heart and Stroke Foundation of Canada., and European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014)

Subjects
Adult, Male, corticosteroid, [SDV]Life Sciences [q-bio], Critical Illness, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], antiplatelet, Lopinavir, Adaptive platform trial randomized controlled trial intensive care, pneumonia COVID-19 antiplatelet immunoglobulin antiviral corticosteroid immune modulation anticoagulation, All institutes and research themes of the Radboud University Medical Center, Adrenal Cortex Hormones, Humans, anticoagulation, intensive care, pneumonia, COVID-19 Serotherapy, Original Investigation, Medicine(all), immune modulation, Ritonavir, SARS-CoV-2, COVID-19, Anticoagulants, Bayes Theorem, General Medicine, Middle Aged, antiviral, Receptors, Interleukin-6, Adaptive platform trial, randomized controlled trial, Female, Human medicine, immunoglobulin, Follow-Up Studies, Hydroxychloroquine
Abstract

ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and ParticipantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and MeasuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and RelevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Published
2023

10. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, YM, Gordon, AC, Derde, LPG, Nichol, AD, Murthy, S, Beidh, FA, Annane, D, Swaidan, LA, Beane, A, Beasley, R, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buxton, M, Buzgau, A, Cheng, A, De Jong, M, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Fowler, R, Girard, TD, Goligher, EC, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Huang, DT, King, AJ, Lamontagne, F, Lawler, PR, Lewis, R, Linstrum, K, Litton, E, Lorenzi, E, Malakouti, S, McAuley, DF, McGlothlin, A, Mcguinness, S, McVerry, BJ, Montgomery, SK, Morpeth, SC, Mouncey, PR, Orr, K, Parke, R, Parker, JC, Patanwala, AE, Rowan, KM, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Tong, SYC, Turgeon, AF, Turner, AM, Van de Veerdonk, FL, Zarychanski, R, Green, C, Berry, S, Marshall, JC, McArthur, C, Angus, DC, Webb, SA, Orford, Neil, Arabi, YM, Gordon, AC, Derde, LPG, Nichol, AD, Murthy, S, Beidh, FA, Annane, D, Swaidan, LA, Beane, A, Beasley, R, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buxton, M, Buzgau, A, Cheng, A, De Jong, M, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Fowler, R, Girard, TD, Goligher, EC, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Huang, DT, King, AJ, Lamontagne, F, Lawler, PR, Lewis, R, Linstrum, K, Litton, E, Lorenzi, E, Malakouti, S, McAuley, DF, McGlothlin, A, Mcguinness, S, McVerry, BJ, Montgomery, SK, Morpeth, SC, Mouncey, PR, Orr, K, Parke, R, Parker, JC, Patanwala, AE, Rowan, KM, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Tong, SYC, Turgeon, AF, Turner, AM, Van de Veerdonk, FL, Zarychanski, R, Green, C, Berry, S, Marshall, JC, McArthur, C, Angus, DC, Webb, SA, and Orford, Neil

Published
2021

11. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Author

Gordon, AC, Al-Beidh, F, Rowan, KM, Nichol, AD, Arabi, YM, Annane, D, Beane, A, Van Bentum-Puijk, W, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Cheng, AC, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Lamontagne, F, Lawler, PR, Leavis, HL, Linstrum, KM, Litton, E, Lorenzi, E, Marshall, JC, Mayr, FB, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Montgomery, SK, Morpeth, SC, Murthy, S, Orr, K, Parke, RL, Parker, JC, Patanwala, AE, Pettill, V, Rademaker, E, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Sligl, WL, Turgeon, AF, Turner, AM, van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Webb, SA, Derde, LPG, Gordon, AC, Al-Beidh, F, Rowan, KM, Nichol, AD, Arabi, YM, Annane, D, Beane, A, Van Bentum-Puijk, W, Berry, LR, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Cheng, AC, Detry, MA, Duffy, EJ, Estcourt, LJ, Fitzgerald, M, Goossens, H, Haniffa, R, Higgins, AM, Hills, TE, Horvat, CM, Lamontagne, F, Lawler, PR, Leavis, HL, Linstrum, KM, Litton, E, Lorenzi, E, Marshall, JC, Mayr, FB, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Montgomery, SK, Morpeth, SC, Murthy, S, Orr, K, Parke, RL, Parker, JC, Patanwala, AE, Pettill, V, Rademaker, E, Santos, MS, Saunders, CT, Seymour, CW, Shankar-Hari, M, Sligl, WL, Turgeon, AF, Turner, AM, van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Webb, SA, and Derde, LPG

Abstract

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CO

Published
2021

12. The association of intensive care with utilization and costs of outpatient healthcare services and quality of life: Results from two independent population-based cohorts

Author

Kosilek, RP, Baumeister, SE, Ittermann, T, Gründling, M, Brunkhorst, FM, Felix, SB, Abel, P, Friesecke, S, Apfelbacher, C, Brandl, M, Schmidt, K, Hoffmann, W, Schmidt, CO, Chenot, JF, Völzke, H, and Gensichen, JS

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Background: Recent studies have indicated that intensive care unit (ICU) treatment is associated with long-term physical and neuropsychiatric impairments. Little is known about outpatient health services use following intensive care. Objective: To examine the association of intensive care with [for full text, please go to the a.m. URL], 53. Kongress für Allgemeinmedizin und Familienmedizin

Published
2019
Full Text
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13. JENA SEPSIS REGISTRY – Sepsisregister für Langzeitverläufe

Author

Schmidt, K, Gensichen, J, Bahr, V, Sakr, Y, Fleischmann, C, Pausch, C, Kortgen, A, Haak, S, Wensing, M, Reinhart, K, and Brunkhorst, FM

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund: Trotz der hohen klinischen und sozioökonomischen Bedeutung der schweren Sepsis existieren weltweit kaum morbiditätspezifische Register. Die wenigen existierenden Sepsis-Register sind meist auf die Phase der stationären Behandlung limitiert. Daten aus der ambulanten Weiterbetreuung[zum vollständigen Text gelangen Sie über die oben angegebene URL], 16. Deutscher Kongress für Versorgungsforschung (DKVF)

Published
2017
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14. Überlebte Sepsis: Welche Kosten entstehen in der Nachsorge?

Author

Hülle, K, Freytag, A, Schmidt, K, Brunkhorst, FM, Hartmann, M, Lehmann, T, Reinhart, K, Schneider, N, Vollmar, HC, and Gensichen, J

Subjects
ddc: 610, Sepsis, Krankheitskostenstudie, 610 Medical sciences, Medicine, Versorgung nach ITS-Aufenthalt
Abstract

Hintergrund: Sepsisüberlebende sind mit schwerwiegenden Langzeitfolgen konfrontiert, bei deren ambulanter Behandlung dem Hausarzt eine Schlüsselposition zukommt. Dies wird in Zukunft aufgrund steigender Fallzahlen zunehmende Bedeutung erlangen. Zur Schaffung eines bedürfnisorientierten[zum vollständigen Text gelangen Sie über die oben angegebene URL], 51. Kongress für Allgemeinmedizin und Familienmedizin

Published
2017
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15. Ergebnisse eines hausarztbasierten Sepsisregisters

Author

Schmidt, K, Gensichen, J, Bahr, V, Fleischmann, C, Haak, S, Kortgen, A, Pausch, C, Reinhart, K, Sakr, Y, Wensing, M, and Brunkhorst, FM

Subjects
allgemeinärztliche Langzeitbetreuung, ddc: 610, Sepsis, Register, 610 Medical sciences, Medicine
Abstract

Hintergrund: Die weltweit wenigen existierenden Sepsis-Register sind meist auf die Phase der stationären Behandlung limitiert. Daten aus der ambulanten Weiterbetreuung sind kaum verfügbar. Somit wird der oft schwere Langzeitverlauf von Sepsis-Überlebenden selten erfasst. Die meisten dieser[zum vollständigen Text gelangen Sie über die oben angegebene URL], 51. Kongress für Allgemeinmedizin und Familienmedizin

Published
2017
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16. Judging quality of current septic shock definitions and criteria

Author

Shankar-Hari, M, Bertolini, G, Brunkhorst, FM, Bellomo, R, Annane, D, Deutschman, CS, Singer, M, Shankar-Hari, M, Bertolini, G, Brunkhorst, FM, Bellomo, R, Annane, D, Deutschman, CS, and Singer, M

Abstract

Septic shock definitions are being revisited. We assess the feasibility, reliability, and validity characteristics of the current definitions and criteria of septic shock. Septic shock is conceptualised as cardiovascular dysfunction, tissue perfusion and cellular abnormalities caused by infection. Currently, for feasibility, septic shock is identified at the bedside by using either hypotension or a proxy for tissue perfusion/cellular abnormalities (e.g., hyperlactatemia). We propose that concurrent presence of cardiovascular dysfunction and perfusion/cellular abnormalities could improve validity of septic shock diagnosis, as we are more likely to identify a patient population with all elements of the illness concept. This epidemiological refinement should not affect clinical care and may aid study design to identify illness-specific biomarkers and interventions.

Published
2015

18. 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI))

Author

Reinhart, K, Brunkhorst, FM, Bone, HG, Bardutzky, J, Dempfle, CE, Forst, H, Gastmeier, P, Gerlach, H, Gründling, M, John, S, Kern, W, Kreymann, G, Krüger, W, Kujath, P, Marggraf, G, Martin, J, Mayer, K, Meier-Hellmann, A, Oppert, M, Putensen, C, Quintel, M, Ragaller, M, Rossaint, R, Seifert, H, Spies, C, Stüber, F, Weiler, N, Weimann, A, Werdan, K, and Welte, T

Subjects
treatment, diagnosis, Deutsche Sepsis-Hilfe, septischer Schock, Prävention, severe sepsis, follow-up care, German Sepsis Aid, Deutsche Sepsis-Gesellschaft, prevention, Diagnose, ddc: 610, septic shock, Nachsorge, Therapie, guideline, German Sepsis Society, Leitlinie, schwere Sepsis
Abstract

Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures for specific clinical circumstances taking into account specific national health care structures. The 1st revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the "German Instrument for Methodological Guideline Appraisal" of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources. Leitlinien sind systematisch entwickelte Darstellungen und Empfehlungen mit dem Zweck, Ärzte und Patienten bei der Entscheidung über angemessene Maßnahmen der Krankenversorgung unter spezifischen medizinischen Umständen und unter Berücksichtigung des spezifischen nationalen Gesundheitssystems zu unterstützen. Die erste Revision der S-2k-Leitlinie der Deutschen Sepsis-Gesellschaft in Kooperation mit 17 weiteren wissenschaftlichen medizinischen Fachgesellschaften und einer Selbsthilfegruppe gibt den Stand des Wissens (Ergebnisse von kontrollierten klinischen Studien und Wissen von Experten) über effektive und angemessene Krankenversorgung zum Zeitpunkt der "Drucklegung" wieder. Die Leitlinienentwicklung erfolgte entsprechend des "Deutschen Instrumentes zur methodischen Leitlinien-Bewertung" der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). In Anbetracht der unausbleiblichen Fortschritte wissenschaftlicher Erkenntnisse und der Technik müssen periodische Überarbeitungen, Erneuerungen und Korrekturen unternommen werden. Die Empfehlungen der Leitlinien können nicht unter allen Umständen angemessen genutzt werden. Die Entscheidung darüber, ob einer bestimmten Empfehlung gefolgt werden soll, muß vom Arzt unter Berücksichtigung der beim individuellen Patienten vorliegenden Gegebenheiten und der verfügbaren Ressourcen getroffen werden.

Published
2010

23. ESPEN Guidelines on Enteral Nutrition: Cardiology and pulmonology

Author

Anker, Sd, John, M, Pedersen, Pu, Raguso, C, Cicoira, Mariantonietta, Dardai, E, Laviano, A, Ponikowski, P, Schols, Am, DGEM GERMAN SOCIETY FOR NUTRITIONAL MEDICINE, Becker, Hf, Bohm, M, Brunkhorst, Fm, Vogelmeier, C, ESPEN EUROPEAN SOCIETY FOR PARENTERAL, and Enteral, Nutrition

Published
2006

25. Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: A multicenter observational study

Author

Bloos, F, Marshall, JC, Dellinger, RP, Vincent, JL, Gutierrez, G, Rivers, E, Balk, RA, Laterre, PF, Angus, DC, Reinhart, K, Brunkhorst, FM, Bloos, F, Marshall, JC, Dellinger, RP, Vincent, JL, Gutierrez, G, Rivers, E, Balk, RA, Laterre, PF, Angus, DC, Reinhart, K, and Brunkhorst, FM

Abstract

Introduction: The intent of this study was to determine whether serum procalcitonin (PCT) levels are associated with prognosis, measured as organ dysfunctions and 28-day mortality, in patients with severe pneumonia.Methods: This was a multicenter, observational study of critically ill adult patients with pneumonia requiring mechanical ventilation conducted in 10 academic hospitals in Canada, the United States, and Central Europe. PCT was measured daily for 14 days using an immuno-luminometric assay.Results: We included 175 patients, 57 with community acquired pneumonia (CAP), 61 with ventilator associated pneumonia (VAP) and 57 with hospital acquired pneumonia (HAP). Initial PCT levels were higher in CAP than VAP patients (median (interquartile range: IQR); 2.4 (0.95 to 15.8) vs. 0.7 (0.3 to 2.15), ng/ml, P < 0.001) but not significantly different to HAP (2.2 (0.4 to 8.0) ng/ml). The 28-day ICU mortality rate for all patients was 18.3% with a median ICU length of stay of 16 days (range 1 to 142 days). PCT levels were higher in non-survivors than in survivors. Initial and maximum PCT levels correlated with maximum Sequential Organ Failure Assessment (SOFA) score r2= 0.50 (95% CI: 0.38 to 0.61) and r2= 0.57 (0.46 to 0.66), respectively. Receiver operating curve (ROC) analysis on discrimination of 28-day mortality showed areas under the curve (AUC) of 0.74, 0.70, and 0.69 for maximum PCT, initial PCT, and Acute Physiology and Chronic Health Evaluation (APACHE) II score, respectively. The optimal cut-off to predict mortality for initial PCT was 1.1 ng/ml (odds ratio: OD 7.0 (95% CI 2.6 to 25.2)) and that for maximum PCT was 7.8 ng/ml (odds ratio 5.7 (95% CI 2.5 to 13.1)).Conclusions: PCT is associated with the severity of illness in patients with severe pneumonia and appears to be a prognostic marker of morbidity and mortality comparable to the APACHE II score. © 2011 Bloos et al.; licensee BioMed Central Ltd.

Published
2011

26. Prevention, diagnosis, therapy and follow-up care of sepsis

Author

Reinhart, K, Brunkhorst, FM, Bone, HG, Bardutzky, J, Dempfle, CE, Forst, H, Gastmeier, P, Gerlach, H, Gründling, M, John, S, Kern, W, Kreymann, G, Krüger, W, Kujath, P, Marggraf, G, Martin, J, Mayer, K, Meier-Hellmann, A, Oppert, M, Putensen, C, Quintel, M, Ragaller, M, Rossaint, R, Seifert, H, Spies, C, Stüber, F, Weiler, N, Weimann, A, Werdan, K, Welte, T, Reinhart, K, Brunkhorst, FM, Bone, HG, Bardutzky, J, Dempfle, CE, Forst, H, Gastmeier, P, Gerlach, H, Gründling, M, John, S, Kern, W, Kreymann, G, Krüger, W, Kujath, P, Marggraf, G, Martin, J, Mayer, K, Meier-Hellmann, A, Oppert, M, Putensen, C, Quintel, M, Ragaller, M, Rossaint, R, Seifert, H, Spies, C, Stüber, F, Weiler, N, Weimann, A, Werdan, K, and Welte, T

Abstract

Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures for specific clinical circumstances taking into account specific national health care structures. The 1st revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the "German Instrument for Methodological Guideline Appraisal" of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources., Leitlinien sind systematisch entwickelte Darstellungen und Empfehlungen mit dem Zweck, Ärzte und Patienten bei der Entscheidung über angemessene Maßnahmen der Krankenversorgung unter spezifischen medizinischen Umständen und unter Berücksichtigung des spezifischen nationalen Gesundheitssystems zu unterstützen. Die erste Revision der S-2k-Leitlinie der Deutschen Sepsis-Gesellschaft in Kooperation mit 17 weiteren wissenschaftlichen medizinischen Fachgesellschaften und einer Selbsthilfegruppe gibt den Stand des Wissens (Ergebnisse von kontrollierten klinischen Studien und Wissen von Experten) über effektive und angemessene Krankenversorgung zum Zeitpunkt der "Drucklegung" wieder. Die Leitlinienentwicklung erfolgte entsprechend des "Deutschen Instrumentes zur methodischen Leitlinien-Bewertung" der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). In Anbetracht der unausbleiblichen Fortschritte wissenschaftlicher Erkenntnisse und der Technik müssen periodische Überarbeitungen, Erneuerungen und Korrekturen unternommen werden. Die Empfehlungen der Leitlinien können nicht unter allen Umständen angemessen genutzt werden. Die Entscheidung darüber, ob einer bestimmten Empfehlung gefolgt werden soll, muß vom Arzt unter Berücksichtigung der beim individuellen Patienten vorliegenden Gegebenheiten und der verfügbaren Ressourcen getroffen werden.

Published
2010

30. Resuscitation fluid use in critically ill adults: an international cross sectional study in 391 intensive care units

Author

Finfer, S, Liu, B, Taylor, C, Bellomo, R, Billot, L, Cook, D, Du, B, Mcarthur, C, Myburgh, J, Jacobs, S, Gazzard, R, Edington, J, Ghelani, D, Blythe, D, Richards, B, Mccalman, C, Parr, M, Walker, C, Seppelt, I, Cole, L, Stevens, D, Cade, J, Webb, S, Woolfe, C, van Heerden PV, Cooper, J, Mitchell, I, Peake, S, French, C, Playford, H, Bannerjee, A, Berwanger, O, da Silva, N, Mario Teles, J, Guimarães, H, Rocha, M, Piras, C, Mcintyre, L, Bagshaw, Sm, Stelfox, T, Green, R, Hall, R, Son, W, Meade, M, Kumar, A, Wittman, R, Martin, C, Leblanc, M, Lim, S, Keenan, S, Magder, S, Chittock, D, Wang, W, Dong, J, Chen, X, Li, A, Zhuang, H, Liu, W, Liu, Y, He, Q, Wang, J, Zhou, N, Bai, Y, Wang, L, Lu, F, Chen, W, Wang, S, Zhou, J, Zhang, Z, Xu, Y, Li, T, Sun, X, Wang, B, Zhao, C, Song, Q, Pan, L, Ma, P, Li, Q, Li, G, Chen, D, Liu, L, Gao, K, Han, S, Wan, X, Zhang, Y, Chao, Y, Xi, X, Jiang, L, Han, C, Qin, T, Jiang, W, Li, Y, Liu, X, Hu, Z, Ding, Y, Li, W, Wang, X, Weng, L, Wang, D, Li, S, An, Y, Zhang, W, Luo, H, Luo, Y, Zhu, X, Li, H, Li, C, Qu, H, Mao, E, Min, D, Wang, C, Zhang, J, Ren, H, Liu, H, Wang, M, Zhao, M, Fei, D, Qian, C, Liu, R, Shi, B, Guo, H, Guan, X, Wu, J, Zhou, L, Yu, K, Wang, H, Wang, Y, Li, D, Huang, Q, Su, M, Dong, C, Zhang, X, Wu, B, Qin, Y, Zhang, N, Kang, Y, Deng, Y, Ai, Y, Guo, Y, Cui, Q, Jia, J, Chen, H, Yan, J, Xu, Q, Sun, R, Hong, J, Fang, Q, Zheng, X, Qiu, H, Liu, S, Zhou, Q, Li, J, Schonemann, N, Bendtsen, A, Thornberg, K, Boensen, H, Tousi, H, Bestle, M, Pawlowicz, M, Høen Beck, D, Carl, P, Ronholm, E, Welling, K, Strelitz, J, Kancir, C, Hostrup, A, Perner, A, Jensen, R, Westergard Nielsen, J, Bennett, S, Ball, A, Becker, H, Desikan, S, Watson, N, Watson, D, Smith, I, Wright, M, Millo, J, Morris, J, Williams, A, Peebles Brown, A, Grainger, K, Marsh, R, Christmas, D, Harling, D, Boulanger, C, Davenport, A, Goldsmith, A, Cook, B, Drage, S, Goodall, J, Higgins, D, Price, J, Margarson, M, Sherry, T, Mcauley, F, Syndercombe, A, Jones, G, Reid, J, Andrivet, P, Jamali, S, Rigaud, J, Gaffine, A, Kerkeni, Mejean, C, Drault, J, Beuret, P, Bourffandeau, B, Gasselin, J, de Jonghe, B, Mercat, A, Quenot, J, Broux, C, Timsit, J, Mokhtar, H, Jacobs, F, Pease, S, Mourvillier, B, Lasocki, S, Clabault, K, Rahmani, H, Cariou, A, Guerin, C, Combes, A, Duguet, A, Thuong, M, Janvier, G, Schortgen, F, Icahai, C, Megarbane, B, Payen, D, Leon, R, Gruson, D, Guidet, B, Tardu, D, Roch, A, Ridel, C, Fartoukh, M, Mentec, H, Guitton, C, Blot, F, Oppert, M, Spies, C, Gründling, M, Friesecke, S, Meier, A, Martin, J, Jaschinski, U, Gärtner, R, Weyland, W, Wappler, F, Bromber, H, Welte, T, Hadem, J, Fiedler, F, Peckelsen, C, Fritz, H, Rensing, H, Ragaller, M, Reinhart, K, Brunkhorst, Fm, Riessen, R, Gerlach, H, Hoffmann, U, Chow, Fl, Cheng, C, Joynt, G, Buckley, T, Auyeung, Kw, Young, K, Ching, Ck, Sigurdsson, S, Sigvaldason, K, Hreinsson, K, Kapadia, F, Donnelly, M, Bailie, R, Breen, D, Bates, J, Marsh, B, Motherway, C, Mcauley, D, Trinder, J, Manzoni, A, Mottura, G, Bonaccorso, G, Luzzani, A, De Blasio, E, Bonanno, R, Cardarelli, N, De Cristofaro, M, Mazzola, E, Monfregola, M, Isetta, M, Franchi, F, Trisolino, F, Marchetti, G, Piga, G, Todesco, L, Perno, S, Bianchin, A, Blasetti, A, Rossi, S, Salcuni, R, Greco, M, Beck, E, Antonini, B, Malacarne, P, Prandi, E, Negro, G, Cubeddu, G, Pasquinucci, G, Ferrari, E, Rotelli, S, Savioli, M, Mediani, T, Tognoli, E, Ribola, A, Laperchia, L, Meinardi, S, Cancellieri, F, Mancosu, S, Segala, V, Gamberini, E, Garofalo, G, Dentini, N, Carnevale, L, Bilotta, F, Brunod, F, Casagrande, L, Riva, I, Osti, D, Sitta, V, Alleva, S, Becattini, G, Munaron, S, Cavallo, R, Marzullo, A, Ferrari, F, Calicchio, G, Sucre, M, Quattrocchi, L, Breschi, C, Gratarola, A, Sciacca, P, Postiglione, M, Barattini, M, Rossi, M, Falcelli, C, Coaloa, M, Cattin, S, Palmese, S, David, Antonio, Calabrese, P, Dote, K, Ohashi, I, Morimatsu, H, Goto, Y, Hagioka, S, Mcguiness, S, Gibson, A, Henderson, S, Freebairn, R, Williams, T, Liang, J, Van Haren, F, Dinsdale, D, Serra, I, Arabi, Y, Qushmaq, I, Abouchala, N, Kherallah, M, Mandourah, Y, Cuthbertson, B, Willis, P, Cole, S, Macdougall, M, Andrews, P, Alcorn, D, Carins, C, Digby, B, Tan, Ck, Lee, P, Chan, Y, Petersen, P, Albert, J, Guldbrand, P, Juhlin Dannfeldt, M, Nielsen, N, Hjelmqvist, H, Nordlund, P, Berkius, J, Oldner, A, Konrad, D, Zatterman, R, Metcalf, K, Friberg, H, Chew, M, Lindgren, K, Aneman, A, Gatz, R, Blomqvist, H, Wizelius, I, Andersson, M, Rodling Wahlstrom, M, Stiernstrom, H, Lindgren, P, Elvstad, T, Hyddmark, U, Merz, T, Laube, M, Haberthuer, C, Jaeggi, M, Maggiorini, M, Stover, J, Ahmed, R, Kellum, J, Murugan, R, Salmon, A, Vlahakis, N, Cohn, S, and Chung, K.

Subjects
Adult, Male, endocrine system, medicine.medical_specialty, Resuscitation, Internationality, Cross-sectional study, Critical Illness, Critical Care and Intensive Care Medicine, complex mixtures, Resuscitation fluid, Intensive care, medicine, Humans, Colloids, Medical prescription, Intensive care medicine, Generalized estimating equation, Aged, critically ill adults, business.industry, Research, digestive, oral, and skin physiology, Odds ratio, Middle Aged, Confidence interval, body regions, Intensive Care Units, Cross-Sectional Studies, intensive care units, Emergency medicine, Commentary, Fluid Therapy, Female, business, Perfusion
Abstract

Introduction Recent evidence suggests that choice of fluid used for resuscitation may influence mortality in critically ill patients. Methods We conducted a cross-sectional study in 391 intensive care units across 25 countries to describe the types of fluids administered during resuscitation episodes. We used generalized estimating equations to examine the association between patient, prescriber and geographic factors and the type of fluid administered (classified as crystalloid, colloid or blood products). Results During the 24-hour study period, 1,955 of 5,274 (37.1%) patients received resuscitation fluid during 4,488 resuscitation episodes. The main indications for administering crystalloid or colloid were impaired perfusion (1,526/3,419 (44.6%) of episodes), or to correct abnormal vital signs (1,189/3,419 (34.8%)). Overall, colloid was administered to more patients (1,234 (23.4%) versus 782 (14.8%)) and during more episodes (2,173 (48.4%) versus 1,468 (32.7%)) than crystalloid. After adjusting for patient and prescriber characteristics, practice varied significantly between countries with country being a strong independent determinant of the type of fluid prescribed. Compared to Canada where crystalloid, colloid and blood products were administered in 35.5%, 40.6% and 28.3% of resuscitation episodes respectively, odds ratios for the prescription of crystalloid in China, Great Britain and New Zealand were 0.46 (95% confidence interval (CI) 0.30 to 0.69), 0.18 (0.10 to 0.32) and 3.43 (1.71 to 6.84) respectively; odds ratios for the prescription of colloid in China, Great Britain and New Zealand were 1.72 (1.20 to 2.47), 4.72 (2.99 to 7.44) and 0.39 (0.21 to 0.74) respectively. In contrast, choice of fluid was not influenced by measures of illness severity (for example, Acute Physiology and Chronic Health Evaluation (APACHE) II score). Conclusions Administration of resuscitation fluid is a common intervention in intensive care units and choice of fluid varies markedly between countries. Although colloid solutions are more expensive and may possibly be harmful in some patients, they were administered to more patients and during more resuscitation episodes than crystalloids were.

Published
2010

33. Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.

Author

Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Gründling M, Moerer O, Riessen R, Seibel A, Ragaller M, Büchler MW, John S, Bach F, Spies C, and Reill L

Abstract

Context: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial.Objective: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction.Design, Setting, and Patients: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group.Interventions: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first.Main Outcome Measure: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days.Results: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43).Conclusion: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure.Trial Registration: clinicaltrials.gov Identifier: NCT00534287. [ABSTRACT FROM AUTHOR]

Published
2012
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34. Update: intensivmedizinische Studien. Ergebnisse der vergangenen 12 Monate.

Author

Knapp J, Marx G, Weismüller K, Steinebach S, Lichtenstern C, Popp E, Mayer K, Brunkhorst FM, Weigand MA, Bernhard M, Knapp, J, Marx, G, Weismüller, K, Steinebach, S, Lichtenstern, C, Popp, E, Mayer, K, Brunkhorst, F M, Weigand, M A, and Bernhard, M

Abstract

Intensive care medicine plays an important role in the medical care of patients as well as the economic success of hospitals. Knowledge and implementation of recent relevant scientific evidence are prerequisites for high quality care in intensive care medicine. The aim of this review is to present an overview of the most important publications in intensive care medicine published in 2010 and the first half of the year 2011 and to comment on their attributable clinical relevance for intensive care practitioners. In 2010 and up to June 2011 many studies with high patient numbers have been published. The main topics were the treatment of respiratory failure, sepsis and investigations to improve analgosedation. [ABSTRACT FROM AUTHOR]

Published
2011
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35. Ergebnisse intensivmedizinischer Studien des Jahres 2009 : Update.

Author

Bernhard M, Marx G, Weismüller K, Lichtenstern C, Mayer K, Brunkhorst FM, Weigand MA, Bernhard, M, Marx, G, Weismüller, K, Lichtenstern, C, Mayer, K, Brunkhorst, F M, and Weigand, M A

Abstract

Critical care medicine plays an important role for the medical and economic success of hospitals. Knowledge and implementation of recent relevant studies are prerequisites for high quality intensive care medicine. The aim of the present manuscript is to present an overview of the most important publications in intensive care medicine in 2009 and comment on their clinical relevance. It has to be recognized that the cited studies are chosen according to the view of the authors. In 2009 many large randomized studies with high patient numbers were published. Main topics in 2009 were the therapy of lung failure, analgosedation and sepsis therapy. New trends are bedside echocardiography and telemedicine. Unfortunately, a magic bullet has not been identified last year. The focus is still on team education and guideline-assisted therapy. [ABSTRACT FROM AUTHOR]

Published
2010
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36. Practice and perception -- a nationwide survey of therapy habits in sepsis.

Author

Brunkhorst FM, Engel C, Ragaller M, Welte T, Rossaint R, Gerlach H, Mayer K, John S, Stuber F, Weiler N, Oppert M, Moerer O, Bogatsch H, Reinhart K, Loeffler M, Hartog C, and German Sepsis Competence Network (SepNet)

Abstract

OBJECTIVE: To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. DESIGN: One-day cross-sectional survey. SETTING: Representative sample of German intensive care units stratified by hospital size. PATIENTS: Adult patients with severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses 'always' and 'frequently' were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation 8 mL/kg predicted body weight. Mean tidal volume was 10.0 +/- 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4-6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels 8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels

Published
2008
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37. Studienprotokoll der VISEP-Studie. Entgegnung der SepNet-Studiengruppe.

Author

Reinhart K, Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, and Kiehntopf M

Abstract

In the commentary by Zander et al. the authors appear concerned about the methods and results of our, at that time, unpublished sepsis trial evaluating hydroxyethyl starch (HES) and insulin therapy. Unfortunately, the authors' concerns are based on false assumptions about the design, conduct and modes of action of the compounds under investigation. For instance, in our study the HES solution was not used for maintenance of daily fluid requirements, so that the assumption of the authors that this colloid was used "exclusively" is wrong. Moreover, the manufacturer of Hemohes, the HES product we used, gives no cut-off value for creatinine, thus the assumption that this cut-off value was "doubled" in our study is also incorrect. Other claims by the authors such as that lactated solutions cause elevated lactate levels, iatrogenic hyperglycemia and increase O(2) consumption are unfounded. There is no randomized controlled trial supporting such a claim - this claim is neither consistent with our study data nor with any credible published sepsis guidelines or with routine practice worldwide. We fully support open scientific debate. Our study methods and results have now been published after a strict peer-reviewing process and this data is now open to critical and constructive reviewing. However, in our opinion this premature action based on wrong assumptions and containing comments by representatives of pharmaceutical companies does not contribute to a serious, unbiased scientific discourse. [ABSTRACT FROM AUTHOR]

Published
2008
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40. Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge

Author

Tomasz Skirecki, Evangelos J. Giamarellos-Bourboulis, Matthijs Kox, F. M. Brunkhorst, Gunnar Lachmann, Stefanie B. Flohé, Ignacio Martin-Loeches, Marcin F. Osuchowski, Jean-Marc Cavaillon, Antoni Torres, Fabienne Venet, Alberto García-Salido, Massimo Girardis, Ignacio Rubio, Joerg C. Schefold, Sebastian Weis, Florian Uhle, André Scherag, Sara Cajander, Ricard Ferrer, Thibaud Spinetti, Mihai G. Netea, Martin Sebastian Winkler, Institut Català de la Salut, [Winkler MS] Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Göttingen, Germany. [Skirecki T] Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, Warsaw, Poland. [Brunkhorst FM] Dept. of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Jena, Germany. Center for Clinical Studies, Jena University Hospital, Jena, Germany. [Cajander S] Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Sweden. [Cavaillon JM] French National Research Agency (ANR), Paris, France. [Ferrer R] Servei de Cures Intensives i Xoc, Grup de Recerca en Disfunció Orgànica i Reanimació, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Instituto de salud Carlos III (ISCIII), Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Medicine (General), Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Review, Pre-clinical research, Vacunes, Mice, 0302 clinical medicine, Animal model, Clinical trial, COVID-19, Pandemic, Vaccine, Cricetinae, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Clinical treatment, Otros calificadores::/terapia [Otros calificadores], mezclas complejas::productos biológicos::vacunas [COMPUESTOS QUÍMICOS Y DROGAS], Clinical Trials as Topic, Age Factors, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], General Medicine, 3. Good health, 030220 oncology & carcinogenesis, Medicine, Primates, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 610 Medicine & health, Antiviral Agents, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, R5-920, COVID-19 (Malaltia) - Tractament, medicine, Animals, Humans, Medical history, Intensive care medicine, Complex Mixtures::Biological Products::Vaccines [CHEMICALS AND DRUGS], SARS-CoV-2, business.industry, Ferrets, Other subheadings::/therapy [Other subheadings], COVID-19 Drug Treatment, Disease Models, Animal, 030104 developmental biology, Clinical research, Clinical evidence, Mutation, Models animals en la investigació, Investigative Techniques::Models, Animal::Investigative Techniques::Disease Models, Animal [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], técnicas de investigación::modelos animales::técnicas de investigación::modelos de enfermedad en animales [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], business
Abstract

Model animal; COVID-19; Recerca preclínica Modelo animal; COVID-19; Investigación preclínica Animal model; COVID-19; Pre-clinical research Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

Published
2021

41. The COSMOS Registry of CytoSorb Hemoadsorption Therapy in Critically Ill Patients: Protocol for an International, Prospective Registry.

Author

Taccone FS, Brunkhorst FM, Bottari G, Hidalgo J, Kribben A, Teboul JL, Tomescu D, Klaus T, Scheier J, Deliargyris E, and Ferrer R

Subjects
Humans, Prospective Studies, Registries, Critical Illness therapy
Abstract

Background: Extracorporeal blood purification with CytoSorb has been increasingly used as an adjunctive therapy in several hyperinflammatory critical care conditions, as well as to remove elevated levels of myoglobin or bilirubin in patients with rhabdomyolysis or liver failure. Despite the increasing worldwide use of hemoadsorption, data from large international multicenter studies are still lacking., Objective: The COSMOS (CytoSorb Treatment Of Critically Ill Patients) registry is a company-sponsored registry by CytoSorbents Corporation and CytoSorbents Medical Inc. and will provide a data repository and reporting infrastructure for the surveillance of CytoSorb use in real-world critical care settings in an unselected, critically ill patient population. The gathered data will serve as a comprehensive resource to assess the effects of such therapy on patients' management., Methods: The international COSMOS registry is collecting prospective data for patients treated with CytoSorb during routine care in various critical care indications, based on the decision of the treating physicians. Data are collected at baseline, during CytoSorb therapy, 24 hours thereafter, at discharge from the intensive care unit and the hospital, and on day 90. Key outcomes assessed include change in inflammatory biomarkers, vasopressor requirements, fluid balance, organ function and organ support, length of intensive care unit and hospital stay, occurrence of adverse events, and mortality., Results: The COSMOS registry started with the inclusion of the first patient on July 15, 2022, and is now actively enrolling in 4 countries (Germany, Spain, Portugal, and Italy), with plans to expand to other countries outside of Europe. An initial readout is planned for presentation at an international Critical Care conference in 2024., Conclusions: The COSMOS registry is intended to provide comprehensive real-world data on patient outcomes with CytoSorb in various critical care indications, thereby contributing to optimization of patient selection, timing of initiation, and dosing of hemoadsorption treatment., Trial Registration: ClinicalTrials.gov NCT05146336; https://clinicaltrials.gov/study/NCT05146336., International Registered Report Identifier (irrid): DERR1-10.2196/55880., (©Fabio Silvio Taccone, Frank Martin Brunkhorst, Gabriella Bottari, Jorge Hidalgo, Andreas Kribben, Jean-Louis Teboul, Dana Tomescu, Teresa Klaus, Joerg Scheier, Efthymios Deliargyris, Ricard Ferrer. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 05.11.2024.)

Published
2024
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42. A Patient-Level Meta-Analysis of Intensive Glucose Control in Critically Ill Adults.

Author

Adigbli D, Li Y, Hammond N, Chatoor R, Devaux AG, Li Q, Billot L, Annane D, Arabi Y, Bilotta F, Bohé J, Brunkhorst FM, Cavalcanti AB, Cook D, Engel C, Green-LaRoche D, He W, Henderson W, Hoedemaekers C, Iapichino G, Kalfon P, de La Rosa G, Lahooti A, Mackenzie I, Mahendran S, Mélot C, Mitchell I, Oksanen T, Polli F, Preiser JC, Garcia Soriano F, Vlok R, Wang L, Xu Y, Delaney AP, Di Tanna GL, and Finfer S

Subjects
Humans, Blood Glucose drug effects, Blood Glucose metabolism, Blood Glucose analysis, Hyperglycemia drug therapy, Hyperglycemia blood, Hyperglycemia mortality, Glycemic Control methods, Adult, Randomized Controlled Trials as Topic, Critical Illness mortality, Hospital Mortality, Hypoglycemia chemically induced
Abstract

Background: Whether intensive glucose control reduces mortality in critically ill patients remains uncertain. Patient-level meta-analyses can provide more precise estimates of treatment effects than are currently available., Methods: We pooled individual patient data from randomized trials investigating intensive glucose control in critically ill adults. The primary outcome was in-hospital mortality. Secondary outcomes included survival to 90 days and time to live cessation of treatment with vasopressors or inotropes, mechanical ventilation, and newly commenced renal replacement. Severe hypoglycemia was a safety outcome., Results: Of 38 eligible trials (n=29,537 participants), 20 (n=14,171 participants) provided individual patient data including in-hospital mortality status for 7059 and 7049 participants allocated to intensive and conventional glucose control, respectively. Of these 1930 (27.3%) and 1891 (26.8%) individuals assigned to intensive and conventional control, respectively, died (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07; P=0.52; moderate certainty). There was no apparent heterogeneity of treatment effect on in-hospital mortality in any examined subgroups. Intensive glucose control increased the risk of severe hypoglycemia (risk ratio, 3.38; 95% CI, 2.99 to 3.83; P<0.0001)., Conclusions: Intensive glucose control was not associated with reduced mortality risk but increased the risk of severe hypoglycemia. We did not identify a subgroup of patients in whom intensive glucose control was beneficial. (Funded by the Australian National Health and Medical Research Council and others; PROSPERO number CRD42021278869.).

Published
2024
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43. Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

Author

Nyvlt P, Schuster FS, Ihlow J, Heeren P, Spies C, Hiesgen J, Schenk T, von Brünneck AC, Westermann J, Brunkhorst FM, La Rosée P, Janka G, Lachmann C, and Lachmann G

Subjects
Humans, Male, Female, Middle Aged, Retrospective Studies, Aged, Adult, Bone Marrow pathology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic etiology, Critical Illness, Ferritins blood, Biomarkers
Abstract

Background: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients., Methods: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and underwent bone marrow biopsy during their ICU course., Results: Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores., Conclusions: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Published
2024
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44. Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.

Author

Thomas-Rüddel D, Bauer M, Moita LF, Helbig C, Schlattmann P, Ehler J, Rahmel T, Meybohm P, Gründling M, Schenk H, Köcher T, Brunkhorst FM, Gräler M, Heger AJ, and Weis S

Subjects
Adult, Female, Humans, Male, Clinical Trials, Phase II as Topic, Dose-Response Relationship, Drug, Double-Blind Method, Randomized Controlled Trials as Topic, Epirubicin administration & dosage, Epirubicin adverse effects, Epirubicin therapeutic use, Sepsis drug therapy, Shock, Septic drug therapy
Abstract

Introduction: Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host-pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose-response trial is necessary to assess the potential harm of this drug in this new indication., Methods and Analysis: Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m 2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive., Ethics and Dissemination: The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT05033808., Competing Interests: Competing interests: LFM is an inventor on an international patent (WO 2013/036153) related to the use of anthracyclines for sepsis treatment. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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45. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine.

Author

Cajander S, Kox M, Scicluna BP, Weigand MA, Mora RA, Flohé SB, Martin-Loeches I, Lachmann G, Girardis M, Garcia-Salido A, Brunkhorst FM, Bauer M, Torres A, Cossarizza A, Monneret G, Cavaillon JM, Shankar-Hari M, Giamarellos-Bourboulis EJ, Winkler MS, Skirecki T, Osuchowski M, Rubio I, Bermejo-Martin JF, Schefold JC, and Venet F

Subjects
Humans, Artificial Intelligence, Goals, Algorithms, Precision Medicine methods, Sepsis diagnosis, Sepsis therapy
Abstract

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes., Competing Interests: Declaration of interests SC reports personal fees from Pfizer, AstraZeneca, Swedish Orphan Biovitrum (SOBI), GSK, and Merck Sharp & Dohme (MSD). MK reports personal fees from ARTCLINE, Atriva, AOP pharma, Inflammatix, and 4TEEN4; and discloses institutional funding from MediSieve, 4TEEN4, Adrenomed, Spinghotec, Cytosorbents, and Inflammatix. MAW reports personal fees from MSD, Gilead, Pfizer, Shionogi, Eumedica, Coulter, Biotest, Sedana, SOBI, and Böhringer; and patent EPA17198330 “Delta-Like Ligand 1 for diagnosing severe infections”. IM-L reports personal fees from MSD, Pfizer, and Gilead. GL reports personal fees from SOBI. EJG-B discloses institutional funding from Abbott, bioMérieux, InflaRx, Johnson & Johnson, MSD, SOBI, XBiotech, Horizon 2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy”, Horizon 2020 European Grants ImmunoSep and RISCinCOVID, and Horizon Health European Grants EPIC-CROWN-2. MSW has received unrestricted funding from Sartorius and reports personal fees from GRIFOLS, Gilead, and Amomed. MO is president of the European Shock Society and Deputy Editor of Intensive Care Medicine Experimental. JFB-M reports personal fees from GSK, PROFARMA programme, Ministry of Industry Spain, GSK-MODUS programme, and Inflammatix; and patents on the following biomarkers related to management of severe infections: PCT/EP2018/064363 “MMP-8 as a marker for identifying infectious disease”, PCT/EP2018/052499 “Pro-ADM as marker indicating an adverse event”, WO2020030745 “Pro-ADM for prognosing the risk of a medical condition requiring hospitalisation in patients with symptoms of infectious disease”, and EP20383140.9 “In vitro method for predicting mortality in COVID-19 patients” (based on detecting N-antigenaemia of SARS-CoV-2 in plasma). JCS discloses institutional funding from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences Services, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestle, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, Pan Gas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GSK, MSD, Eli Lilly and Company, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Philips Medical, Prolong Pharmaceuticals and Nycomed, Phagenesis, and Cytel, outside of the submitted work. JCS is Chair of the Clinical Advisory Board of Hemotune. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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46. Simvastatin in Critically Ill Patients with Covid-19.

Author

Hills TE, Lorenzi E, Berry LR, Shyamsundar M, Al-Beidh F, Annane D, Arabi Y, Aryal D, Au C, Beane A, Bhimani Z, Bonten M, Bradbury CA, Brunkhorst FM, Burrell A, Buxton M, Calfee CS, Cecconi M, Cheng AC, Cove ME, Detry MA, Estcourt LJ, Fitzgerald M, Goligher EC, Goossens H, Green C, Haniffa R, Harrison DA, Hashmi M, Higgins AM, Horvat C, Huang DT, Ichihara N, Jayakumar D, Kruger PS, Lamontagne F, Lampro L, Lawler PR, Marshall JC, Mason AJ, McGlothlin A, McGuinness S, McQuilten ZK, McVerry BJ, Mouncey PR, Murthy S, Neal MD, Nichol AD, O'Kane CM, Parke RL, Parker JC, Rabindrarajan E, Reyes LF, Rowan KM, Saito H, Santos M, Saunders CT, Seymour CW, Shankar-Hari M, Sinha P, Thompson BT, Turgeon AF, Turner AM, van de Veerdonk F, Weis S, Young IS, Zarychanski R, Lewis RJ, McArthur CJ, Angus DC, Berry SM, Derde LPG, Webb SA, Gordon AC, and McAuley DF

Subjects
Humans, Bayes Theorem, COVID-19 Drug Treatment, Hospital Mortality, Treatment Outcome, COVID-19 mortality, COVID-19 therapy, Critical Illness mortality, Critical Illness therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Simvastatin therapeutic use
Abstract

Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear., Methods: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2)., Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control., Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)., (Copyright © 2023 Massachusetts Medical Society.)

Published
2023
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47. [Laboratory and calorimetric monitoring of medical nutrition therapy in intensive and intermediate care units : Second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI)].

Author

Elke G, Hartl WH, Adolph M, Angstwurm M, Brunkhorst FM, Edel A, Heer G, Felbinger TW, Goeters C, Hill A, Kreymann KG, Mayer K, Ockenga J, Petros S, Rümelin A, Schaller SJ, Schneider A, Stoppe C, and Weimann A

Subjects
Adult, Humans, Critical Care, Critical Illness therapy, Intensive Care Units, Nutrition Therapy, Emergency Medicine
Abstract

This second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) provides recommendations on the laboratory monitoring of macro- and micronutrient intake as well as the use of indirect calorimetry in the context of medical nutrition therapy of critically ill adult patients. In addition, recommendations are given for disease-related or individual (level determination) substitution and (high-dose) pharmacotherapy of vitamins and trace elements., (© 2023. The Author(s).)

Published
2023
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48. Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Author

Adhikari NKJ, Hashmi M, Tirupakuzhi Vijayaraghavan BK, Haniffa R, Beane A, Webb SA, Angus DC, Gordon AC, Cook DJ, Guyatt GH, Berry LR, Lorenzi E, Mouncey PR, Au C, Pinto R, Ménard J, Sprague S, Masse MH, Huang DT, Heyland DK, Nichol AD, McArthur CJ, de Man A, Al-Beidh F, Annane D, Anstey M, Arabi YM, Battista MC, Berry S, Bhimani Z, Bonten MJM, Bradbury CA, Brant EB, Brunkhorst FM, Burrell A, Buxton M, Cecconi M, Cheng AC, Cohen D, Cove ME, Day AG, Derde LPG, Detry MA, Estcourt LJ, Fagbodun EO, Fitzgerald M, Goossens H, Green C, Higgins AM, Hills TE, Horvat C, Ichihara N, Jayakumar D, Kanji S, Khoso MN, Lawler PR, Lewis RJ, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, McQuilten ZK, McVerry BJ, Murthy S, Parke RL, Parker JC, Reyes LF, Rowan KM, Saito H, Salahuddin N, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Tolppa T, Trapani T, Turgeon AF, Turner AM, Udy AA, van de Veerdonk FL, Zarychanski R, and Lamontagne F

Subjects
Humans, Female, Middle Aged, Male, Ascorbic Acid therapeutic use, Critical Illness therapy, Critical Illness mortality, Hospital Mortality, Bayes Theorem, Randomized Controlled Trials as Topic, Vitamins therapeutic use, COVID-19, Sepsis drug therapy
Abstract

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain., Objective: To determine whether vitamin C improves outcomes for patients with COVID-19., Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents., Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses)., Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility., Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy., Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival., Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Published
2023
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49. Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis.

Author

Adigbli D, Yang L, Hammond N, Annane D, Arabi Y, Bilotta F, Bohé J, Brunkhorst FM, Cavalcanti AB, Cook D, Engel C, Green-LaRoche D, He W, Henderson W, Hoedemaekers C, Iapichino G, Kalfon P, Rosa G, MacKenzie I, Mélot C, Mitchell I, Oksanen T, Polli F, Preiser JC, Soriano FG, Wang LC, Yuan J, Delaney A, Tanna GLD, and Finfer S

Subjects
Adult, Humans, Bayes Theorem, Systematic Reviews as Topic, Administration, Intravenous, Meta-Analysis as Topic, Blood Glucose, Critical Illness
Abstract

Objective: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults., Data Sources: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available., Methods: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge., Primary Endpoint: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used., Discussion: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?'Protocol version 0.4 - 06/26/2023PROSPERO registration:CRD42021278869.

Published
2023
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50. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Author

Lawler PR, Derde LPG, van de Veerdonk FL, McVerry BJ, Huang DT, Berry LR, Lorenzi E, van Kimmenade R, Gommans F, Vaduganathan M, Leaf DE, Baron RM, Kim EY, Frankfurter C, Epelman S, Kwan Y, Grieve R, O'Neill S, Sadique Z, Puskarich M, Marshall JC, Higgins AM, Mouncey PR, Rowan KM, Al-Beidh F, Annane D, Arabi YM, Au C, Beane A, van Bentum-Puijk W, Bonten MJM, Bradbury CA, Brunkhorst FM, Burrell A, Buzgau A, Buxton M, Cecconi M, Cheng AC, Cove M, Detry MA, Estcourt LJ, Ezekowitz J, Fitzgerald M, Gattas D, Godoy LC, Goossens H, Haniffa R, Harrison DA, Hills T, Horvat CM, Ichihara N, Lamontagne F, Linstrum KM, McAuley DF, McGlothlin A, McGuinness SP, McQuilten Z, Murthy S, Nichol AD, Owen DRJ, Parke RL, Parker JC, Pollock KM, Reyes LF, Saito H, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Singh V, Turgeon AF, Turner AM, Zarychanski R, Green C, Lewis RJ, Angus DC, Berry S, Gordon AC, McArthur CJ, and Webb SA

Subjects
Female, Humans, Male, Middle Aged, Bayes Theorem, Hospitalization, Critical Illness, Receptors, Chemokine antagonists & inhibitors, Angiotensin Receptor Antagonists pharmacology, Angiotensin Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors pharmacology, Angiotensin-Converting Enzyme Inhibitors therapeutic use, COVID-19 therapy, Renin-Angiotensin System drug effects, COVID-19 Drug Treatment methods
Abstract

Importance: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19., Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19., Design, Setting, and Participants: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022)., Interventions: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days., Main Outcomes and Measures: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes., Results: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively)., Conclusions and Relevance: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2023
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