Pierre Asfar1, Frédérique Schortgen2, Julie Boisramé-Helms3, Julien Charpentier4, Emmanuel Guérot5, Bruno Megarbane6, David Grimaldi7, Fabien Grelon8, Nadia Anguel9, Sigismond Lasocki10, Matthieu Henry-Lagarrigue11, Frédéric Gonzalez12, François Legay13, Christophe Guitton14, Maleka Schenck15, Jean Marc Doise16, Jérôme Devaquet17, Thierry Van Der Linden18, Delphine Chatellier19, Jean Philippe Rigaud20, Jean Dellamonica21, Fabienne Tamion22, Ferhat Meziani3, Alain Mercat23, Didier Dreyfuss24, Valérie Seegers25, Peter Radermacher26. 1. Département de Réanimation Médicale et de Médecine Hyperbare, Angers, France. Electronic address: piasfar@chu-angers.fr. 2. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Henri Mondor, APHP, Créteil, France. 3. Service de Réanimation Médicale, Nouvel Hôpital Civil, Centre Hospitalo-Universitaire, Strasbourg, France. 4. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Cochin, APHP, Paris, France. 5. Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, APHP, Paris, France. 6. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Lariboisière, APHP, France. 7. Service de Réanimation, Centre Hospitalier Angré Mignot, Le Chesnay, France. 8. Service de Réanimation, Centre hospitalier, Le Mans, France. 9. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Le Kremlin Bicêtre, APHP, France. 10. Département d'Anesthésie Réanimation, Centre Hospitalo-Universitaire, Angers, France. 11. Service de Réanimation, Centre Hospitalier, La Roche sur Yon, France. 12. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Avicenne, APHP, France. 13. Service de Réanimation, Centre Hospitalier, Saint Brieuc, France. 14. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Nantes, France. 15. Service de Réanimation Médicale, Hôpital de Hautepierre, Centre Hospitalo-Universitaire, Strasbourg, France. 16. Service de Réanimation, Centre Hospitalier, Chalon sur Saône, France. 17. Service de Réanimation, Hôpital Foch, Suresnes, France. 18. Service de Réanimation, Centre Hospitalier Saint Philibert, Lomme, France. 19. Service de Réanimation Médicale, Centre Hospitalo-Universitaire, Poitiers, Paris, France. 20. Service de Réanimation, Centre Hospitalier, Dieppe, France. 21. Service de Réanimation, Centre Hospitalier-Universitaire, Nice, France. 22. Service de Réanimation Médicale, Centre Hospitalier-Universitaire, Rouen, France. 23. Département de Réanimation Médicale et de Médecine Hyperbare, Angers, France. 24. Service de Réanimation Médicale, Centre Hospitalo-Universitaire Louis Mourier, APHP, Paris, France. 25. Department of Statistics, Institut de Cancérologie de l'Ouest, Angers, France. 26. Institut für anesthesiologische Pathophysiologie und Verfahrensentwicklung, Universitätklinikum Ulm, Ulm, Germany.
Abstract
BACKGROUND: There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO2) and fluid resuscitation with hypertonic saline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality. METHODS: This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO2 at 1·0 (hyperoxia) or FiO2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422. FINDINGS:Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23). INTERPRETATION: In patients with septic shock, setting FiO2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival. FUNDING: The French Ministry of Health.
RCT Entities:
BACKGROUND: There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO2) and fluid resuscitation with hypertonicsaline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality. METHODS: This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO2 at 1·0 (hyperoxia) or FiO2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422. FINDINGS: Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23). INTERPRETATION: In patients with septic shock, setting FiO2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival. FUNDING: The French Ministry of Health.
Authors: Neil R Aggarwal; Roy G Brower; David N Hager; B Taylor Thompson; Giora Netzer; Carl Shanholtz; Adrian Lagakos; William Checkley Journal: Crit Care Med Date: 2018-04 Impact factor: 7.598
Authors: Mark J Peters; Gareth A L Jones; Daisy Wiley; Jerome Wulff; Padmanabhan Ramnarayan; Samiran Ray; David Inwald; Michael Grocott; Michael Griksaitis; John Pappachan; Lauran O'Neill; Simon Eaton; Paul R Mouncey; David A Harrison; Kathryn M Rowan Journal: Intensive Care Med Date: 2018-06-04 Impact factor: 17.440