Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Mebazaa, A.; Geven, C.; Hollinger, A.; Wittebole, X.; Chousterman, B. G.; Blet, A.; Gayat, E.; Hartmann, O.; Scigalla, P.; Struck, J.; Bergmann, A.; Antonelli, M.; Beishuizen, A.; Constantin, J. -M.; Damoisel, C.; Deye, N.; Di Somma, S.; Dugernier, T.; Francois, B.; Gaudry, S.; Huberlant, V.; Lascarrou, J. -B.; Marx, G.; Mercier, E.; Oueslati, H.; Pickkers, P.; Sonneville, R.; Legrand, M.; Laterre, P. -F.; Laterre, P. F.; Berghe, C.; Dujardin, M. -F.; Renard, S.; Collienne, C.; Zapatero, D. C.; Vinetti, M.; De Schryver, N.; Thirifays, A.; Mairesse, J.; Petre, H.; Buelens, I.; Henin, P.; Trine, H.; Laurent, Y.; Sebastien, L.; Geukens, P.; Kehl, L.; Vignon, P.; Pichon, N.; Begot, E.; Fedou, A. -L.; Chapellas, C.; Galy, A.; Rodier, N.; Baudrillart, L.; Nouaille, M.; Laleu, S.; Mancia, C.; Daix, T.; Bourzeix, P.; Herafa, I.; Duchambon, A. -A.; Lascarrou, J. B.; Fiancette, M.; Colin, G.; Henry-Lagarrigue, M.; Lacherade, J. -C.; Lebert, C.; Martin-Levevre, L.; Vinatier, I.; Yehia, A.; Bachoumas, K.; Joret, A.; Reignier, J.; Rousseau, C.; Maquigneau, N.; Alcourt, Y.; Zinzonni, V. E.; Deschamps, A.; Robert, A.; Simeon-Vieules, V.; Aubrey, A.; Mabilat, C.; Garot, D.; Ehrmann, S.; Legras, A.; Jouan, Y.; Dequin, P. F.; Guillon, A.; Bodet-Contentin, L.; Rouve, E.; Salmon, C.; Brick, L.; Massat, S.; Desachy, A.; Fally, M. A.; Robin, L.; Cracco, C.; Lafon, C.; Calvat, S.; Rouleau, S.; Schnell, D.; Lasocki, S.; Fesard, P.; Leblanc, D.; Bouhours, G.; Chassier, C.; Conte, M.; Gaillard, T.; Denou, F.; Kerymel, M.; Guyon, M.; Loiez, A.; Lebreton, S.; Meziani, F.; Allam, H.; Chenaf, S.; Rahmani, H.; Heenen, S.; Kummerlen, C.; Delabranche, X.; Boivin, A.; Clere-Jehl, R.; Rabouel, Y.; Pottecher, J.; Bayer, S.; Metzger, C.; Hecketsweiler, S.; Ludes, P. O.; Besancenot, H.; Dhif, N.; Freys, G.; Lessinger, J. -M.; Launoy, A.; Ruimy, A.; Meyer, A.; Szozot, M.; Fournier, M. -C.; Abroug, S.; Louadah, B.; Feliot, E.; Voicu, S.; Malissin, I.; Megarbane, B.; Manivet, P.; Victori, G.; Kelly, D. S.; La Foucher, B.; Pierre, V.; Kerdjana, L.; Beeken, T.; Goury, A.; Garcon, P.; Gaugain, S.; Huot, B.; Barthelemy, R.; Soyer, B.; Jacob, L.; Bonnet, F.; Legall, C.; Cupaciu, A.; Letrou, S.; Bouadma, L.; Mourvillier, B.; Deiler, V.; Magalhaes, E.; Neuville, M.; Timsit, J. -F.; Radjou, A.; Dubief, E.; Messika, J.; La Combe, B.; Roux, D.; Berquier, G.; Laissi, M.; Ricard, J. -D.; Perbet, S.; Delmas, J.; Pascal, J.; Cayot, S.; Guerin, R.; Jabaudon, M.; Roszyk, L.; Rolhion, C.; Bourdier, J.; Lematte, M.; Gouhier, C.; Verlhac, C.; Godet, T.; Radji, S.; Caumon, E.; Thibault, S.; Marx, N.; Schuerholz, T.; Pezechk, J.; Feld, F.; Brulls, C.; Beeker, T.; Simon, T. -P.; Deisz, R.; Schindler, A.; Meier, B.; Janisch, T.; Hohn, A.; Schedler, D.; Wetsch, W.; Schroder, D.; Meier-Hellmann, A.; Lucht, A.; Henker, R.; Rommer, M.; Meinig, T.; Zacharowski, K. D.; Meybohm, P.; Lindau, S.; Mutlak, H.; Kluge, S.; Ringeis, G.; Fullekrug, B.; Singer, B.; Nierhaus, A.; Bangert, K.; De Heer, G.; Frings, D.; Fuhrmann, V.; Muller, J.; Schreiber, J.; Sensen, B.; Siedler, S.; Siewecke, A.; Soffker, G.; Wichmann, D.; Kerinn, M.; Jaschinski, U.; Kreuser, I.; Zanquila, M.; Kortgen, A.; Bloos, F.; Gonnert, F.; Thomas-Ruddel, D.; Haucke, A.; Kolanos, S.; Kohlberg, K. K.; Bloos, P.; Schwope, K.; Russo, V.; Simona, S.; Bartoli, C.; Navarin, S.; Bongiovanni, C.; Orru, M.; Quatrocchi, D.; Zoccoli, G.; Varchetta, A.; Vallecoccia, M. S.; Cutuli, S. L.; Digravio, V.; Quattrochi, D.; D'Arrigo, S.; Leone, F. E.; Beishuizen, B.; Rinket, M.; Border, N.; Bos-Burgmeijer, M.; Braad, A.; Papendorp, S.; Cornet, A.; Vermeijden, J.; Trof, R. J.; Van Wezel, H.; Heunks, L.; Hoedemaekers, A.; Van Der Hoeven, H.; Roovers, N.; Hemelaar, P.

doi:10.1186/s13054-018-2243-2

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study / Mebazaa, A.; Geven, C.; Hollinger, A.; Wittebole, X.; Chousterman, B. G.; Blet, A.; Gayat, E.; Hartmann, O.; Scigalla, P.; Struck, J.; Bergmann, A.; Antonelli, M.; Beishuizen, A.; Constantin, J. -M.; Damoisel, C.; Deye, N.; Di Somma, S.; Dugernier, T.; Francois, B.; Gaudry, S.; Huberlant, V.; Lascarrou, J. -B.; Marx, G.; Mercier, E.; Oueslati, H.; Pickkers, P.; Sonneville, R.; Legrand, M.; Laterre, P. -F.; Laterre, P. F.; Berghe, C.; Dujardin, M. -F.; Renard, S.; Collienne, C.; Zapatero, D. C.; Vinetti, M.; De Schryver, N.; Thirifays, A.; Mairesse, J.; Petre, H.; Buelens, I.; Henin, P.; Trine, H.; Laurent, Y.; Sebastien, L.; Geukens, P.; Kehl, L.; Vignon, P.; Pichon, N.; Begot, E.; Fedou, A. -L.; Chapellas, C.; Galy, A.; Rodier, N.; Baudrillart, L.; Nouaille, M.; Laleu, S.; Mancia, C.; Daix, T.; Bourzeix, P.; Herafa, I.; Duchambon, A. -A.; Lascarrou, J. B.; Fiancette, M.; Colin, G.; Henry-Lagarrigue, M.; Lacherade, J. -C.; Lebert, C.; Martin-Levevre, L.; Vinatier, I.; Yehia, A.; Bachoumas, K.; Joret, A.; Reignier, J.; Rousseau, C.; Maquigneau, N.; Alcourt, Y.; Zinzonni, V. E.; Deschamps, A.; Robert, A.; Simeon-Vieules, V.; Aubrey, A.; Mabilat, C.; Garot, D.; Ehrmann, S.; Legras, A.; Jouan, Y.; Dequin, P. F.; Guillon, A.; Bodet-Contentin, L.; Rouve, E.; Salmon, C.; Brick, L.; Massat, S.; Desachy, A.; Fally, M. A.; Robin, L.; Cracco, C.; Lafon, C.; Calvat, S.; Rouleau, S.; Schnell, D.; Lasocki, S.; Fesard, P.; Leblanc, D.; Bouhours, G.; Chassier, C.; Conte, M.; Gaillard, T.; Denou, F.; Kerymel, M.; Guyon, M.; Loiez, A.; Lebreton, S.; Meziani, F.; Allam, H.; Chenaf, S.; Rahmani, H.; Heenen, S.; Kummerlen, C.; Delabranche, X.; Boivin, A.; Clere-Jehl, R.; Rabouel, Y.; Pottecher, J.; Bayer, S.; Metzger, C.; Hecketsweiler, S.; Ludes, P. O.; Besancenot, H.; Dhif, N.; Freys, G.; Lessinger, J. -M.; Launoy, A.; Ruimy, A.; Meyer, A.; Szozot, M.; Fournier, M. -C.; Abroug, S.; Louadah, B.; Feliot, E.; Voicu, S.; Malissin, I.; Megarbane, B.; Manivet, P.; Victori, G.; Kelly, D. S.; La Foucher, B.; Pierre, V.; Kerdjana, L.; Beeken, T.; Goury, A.; Garcon, P.; Gaugain, S.; Huot, B.; Barthelemy, R.; Soyer, B.; Jacob, L.; Bonnet, F.; Legall, C.; Cupaciu, A.; Letrou, S.; Bouadma, L.; Mourvillier, B.; Deiler, V.; Magalhaes, E.; Neuville, M.; Timsit, J. -F.; Radjou, A.; Dubief, E.; Messika, J.; La Combe, B.; Roux, D.; Berquier, G.; Laissi, M.; Ricard, J. -D.; Perbet, S.; Delmas, J.; Pascal, J.; Cayot, S.; Guerin, R.; Jabaudon, M.; Roszyk, L.; Rolhion, C.; Bourdier, J.; Lematte, M.; Gouhier, C.; Verlhac, C.; Godet, T.; Radji, S.; Caumon, E.; Thibault, S.; Marx, N.; Schuerholz, T.; Pezechk, J.; Feld, F.; Brulls, C.; Beeker, T.; Simon, T. -P.; Deisz, R.; Schindler, A.; Meier, B.; Janisch, T.; Hohn, A.; Schedler, D.; Wetsch, W.; Schroder, D.; Meier-Hellmann, A.; Lucht, A.; Henker, R.; Rommer, M.; Meinig, T.; Zacharowski, K. D.; Meybohm, P.; Lindau, S.; Mutlak, H.; Kluge, S.; Ringeis, G.; Fullekrug, B.; Singer, B.; Nierhaus, A.; Bangert, K.; De Heer, G.; Frings, D.; Fuhrmann, V.; Muller, J.; Schreiber, J.; Sensen, B.; Siedler, S.; Siewecke, A.; Soffker, G.; Wichmann, D.; Kerinn, M.; Jaschinski, U.; Kreuser, I.; Zanquila, M.; Kortgen, A.; Bloos, F.; Gonnert, F.; Thomas-Ruddel, D.; Haucke, A.; Kolanos, S.; Kohlberg, K. K.; Bloos, P.; Schwope, K.; Russo, V.; Simona, S.; Bartoli, C.; Navarin, S.; Bongiovanni, C.; Orru, M.; Quatrocchi, D.; Zoccoli, G.; Varchetta, A.; Vallecoccia, M. S.; Cutuli, S. L.; Digravio, V.; Quattrochi, D.; D'Arrigo, S.; Leone, F. E.; Beishuizen, B.; Rinket, M.; Border, N.; Bos-Burgmeijer, M.; Braad, A.; Papendorp, S.; Cornet, A.; Vermeijden, J.; Trof, R. J.; Van Wezel, H.; Heunks, L.; Hoedemaekers, A.; Van Der Hoeven, H.; Roovers, N.; Hemelaar, P.. - In: CRITICAL CARE. - ISSN 1466-609X. - 22:1(2018). [10.1186/s13054-018-2243-2]