title: Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial.
abstract: 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.
  
  
  
  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 FiO2at 1·0 (hyperoxia) or FiO2set 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.
  
  
  
  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).
  
  
  
  In patients with septic shock, setting FiO2to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival.
  
  
  
  The French Ministry of Health.
authors.affiliation: Département de Réanimation Médicale et de Médecine Hyperbare, Angers, France. Electronic address: piasfar@chu-angers.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Asfar
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Henri Mondor, APHP, Créteil, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Schortgen
authors.affiliation: Service de Réanimation Médicale, Nouvel Hôpital Civil, Centre Hospitalo-Universitaire, Strasbourg, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Boisramé-Helms
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Cochin, APHP, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Charpentier
authors.affiliation: Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, APHP, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guérot
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Lariboisière, APHP, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Megarbane
authors.affiliation: Service de Réanimation, Centre Hospitalier Angré Mignot, Le Chesnay, France.
authors.forename: David
authors.initials: D
authors.lastname: Grimaldi
authors.affiliation: Service de Réanimation, Centre hospitalier, Le Mans, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Grelon
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Le Kremlin Bicêtre, APHP, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Anguel
authors.affiliation: Département d'Anesthésie Réanimation, Centre Hospitalo-Universitaire, Angers, France.
authors.forename: Sigismond
authors.initials: S
authors.lastname: Lasocki
authors.affiliation: Service de Réanimation, Centre Hospitalier, La Roche sur Yon, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Henry-Lagarrigue
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Avicenne, APHP, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gonzalez
authors.affiliation: Service de Réanimation, Centre Hospitalier, Saint Brieuc, France.
authors.forename: François
authors.initials: F
authors.lastname: Legay
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Nantes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guitton
authors.affiliation: Service de Réanimation Médicale, Hôpital de Hautepierre, Centre Hospitalo-Universitaire, Strasbourg, France.
authors.forename: Maleka
authors.initials: M
authors.lastname: Schenck
authors.affiliation: Service de Réanimation, Centre Hospitalier, Chalon sur Saône, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Doise
authors.affiliation: Service de Réanimation, Hôpital Foch, Suresnes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devaquet
authors.affiliation: Service de Réanimation, Centre Hospitalier Saint Philibert, Lomme, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Van Der Linden
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire, Poitiers, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Chatellier
authors.affiliation: Service de Réanimation, Centre Hospitalier, Dieppe, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Rigaud
authors.affiliation: Service de Réanimation, Centre Hospitalier-Universitaire, Nice, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Dellamonica
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalier-Universitaire, Rouen, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tamion
authors.affiliation: Service de Réanimation Médicale, Nouvel Hôpital Civil, Centre Hospitalo-Universitaire, Strasbourg, France.
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
authors.affiliation: Département de Réanimation Médicale et de Médecine Hyperbare, Angers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Mercat
authors.affiliation: Service de Réanimation Médicale, Centre Hospitalo-Universitaire Louis Mourier, APHP, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Dreyfuss
authors.affiliation: Department of Statistics, Institut de Cancérologie de l'Ouest, Angers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Seegers
authors.affiliation: Institut für anesthesiologische Pathophysiologie und Verfahrensentwicklung, Universitätklinikum Ulm, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
mesh_terms: D000368:Aged; D005260:Female; D005440:Fluid Therapy / Q000379:methods*; D005602:France; D006801:Humans; D018496:Hyperoxia / Q000209:etiology / Q000401:mortality / Q000628:therapy*; D007362:Intensive Care Units; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D012121:Respiration, Artificial; D012151:Resuscitation / Q000379:methods*; D012462:Saline Solution, Hypertonic / Q000009:adverse effects*; D012772:Shock, Septic / Q000150:complications / Q000401:mortality / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D012462:Saline Solution, Hypertonic