Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial
Authors: Robba Chiara , Badenes Rafael , Battaglini Denise , Ball Lorenzo , Sanfilippo Filippo , Brunetti Iole , Jakobsen Janus Christian , Lilja Gisela , Friberg Hans , Wendel-Garcia Pedro David , Young Paul J. , Eastwood Glenn , Chew Michelle S. , Unden Johan , Thomas Matthew , Joannidis Michael , Nichol Alistair , Lundin Andreas , Hollenberg Jacob , Hammond Naomi , Saxena Manoj , Martin Annborn , Solar Miroslav , Taccone Fabio Silvio , Dankiewicz Josef , Nielsen Niklas , Grejs Anders Morten , Ebner Florian , Pelosi Paolo ,   TTM2 Trial collaborators, Bělohlávek Jan , Callaway Clifton , Cariou Alain , Cronberg Tobias , Erlinge David , Hovdenes Jan , Kirkegaard Hans , Levin Helena , Morgan Matt P. G. , Nordberg Per , Oddo Mauro , Rylander Christian , Storm Christian , Ullén Susann , Wise Matt P. , Rowan Kathy , Harrison David , Mouncey Paul , Shankar-Hari Manu , Young Duncan , Lange Theis , Palmér Karolina , Karlsson Ulla-Britt , Heissler Simon , Bass Frances , Myburgh John , Taylor Colman , Bellino Adele , Abel-all Marwa , Finfer Ben , Koch Carolyn , Li Yang , O’Connor Anne , Pilowsky Julia , Schneider Tina , Tippett Anna , Ady Bridget , Broadley Tessa , Brown Amanda , Melgaard Liz , Morgan Mimi , Singh Vanessa , Symons Rebecca , Becker Kathrin , Sante Nathalie , Saleova Vendula , Zerzanova Silvie , Sefir-Kribel Samia , Lübeck Ute , Carrara Martina , Fernando Kathryn , Mackle Diane , Navarra Leanlove , Riley Judith , Westerheim Elin , Flatebø Marianne , Ceric Ameldina , Haxhija Zana , Terling Lovisa , Bossmar Lena , Jergle Liz , Månsson Helén Holm , Maillard Samia Abed , Zagar Andreja Vujicic , Jodlauk Christina , Scrivens Jennifer , Ainscough Kate , Fahey Ciara , Bellomo Rinaldo , Peck Leah , Young Helen , Cheung Winston , Cross Rosalba , Hayes Michael , Jain Nitin , Kol Mark , Shah Asim , Wagh Atul , Wong Helen , Eduardo Martinez F. , Brinkerhoff Gail , Bush Dustin , Stewart Antony , Aneman Anders , Lombardo Lien , McCanny Peter , Penketh James , Seppelt Ian , Gresham Rebecca , Lowrey Julie , Masters Kristy , Whitehead Christina , Walsham James , Harward Meg , Mackay Josephine , Meyer Jason , Saylor Emma , Venz Ellen , Wetzig Krista , Stedman Wade , Ashelford Angela , Mar Sharon , Tokumitsu Miyuki , Yarad Elizabeth , Buscher Hergen , Reynolds Claire , Udy Andrew , Burrell Aidan , Collins Jasmin , Gantner Dashiell , Martin Victoria Emma-Leah , Mccracken Phoebe , Nanjayya Vinodh , Richardson Alexander Sacha , Young Meredith , Ghosh Angaj , Said Simone , Beer Ronny , Hartig Frank , Helbok Raimund , Klein Sebastian , Peer Andreas , Creteur Jacques , Durand Dominique , Dupont Matthias , Christiaens Sigrid , Claes Carola , Deckx Sebastiaan , Ferdinande Bert , Lenaerts Sanne , Mullens Wilifred , Stroobants Sarah , Theunissen Evi , Verhaert David , Šmíd Ondřej , Flaksa Marek , Kemlink David , Malík Jan , Otáhal Michal , Rulíšek Jan , Šíranec Michal , Stach Zdeněk , Valeriánová Anna , Zavadilova Petra , Solař Miroslav , Bánszky Róber , Červená Jana , Pařízková Renata Černá , Šimůnek Libor , Varhaník Filip , Karásek Jiří , Strýček Matěj , Grejs Anders , Christensen Steffen , Juhl-Olsen Peter , Thomsen Ida Katrine , Østergaard Lisa Gregersen , Cao Albert , Dupland Pierre , Gavaud Ariane , Jaubert Paul , Jozwiak Mathieu , Marin Nathalie , Savary Guillaume , Deye Nicolas , Megarbane Bruno , Mora Pierre , Sutterlin Laetitia , Legriel Stephane , Bellut Hugo , Ferre Alexis , Lacave Guillaume , Paul Marine , Lascarrou Jean-Baptiste , Canet Emmanuel , Garret Charlotte , Miaihle Arnaud Felix , Reignier Jean , Vignon Philippe , Daix Thomas , Desachy Arnaud , Evrard Bruno , Francois Bruno , Fedou Anne-Laure , Goudelin Marine , Leithner Christoph , Nee Jens , Streitberger Kaspar Josche , Bonatti Giulia , Firpo Iacopo , Frisoni Paolo , Iachi Arianna , Maiani Simona , Mandelli Maura , Tarantino Fabio , Barbieri Alberto , Bertellini Elisabetta , Giuliani Enrico , Melegari Gabriele , Roman-Pognuz Erik , Berlot Giorgio , Lucangelo Umberto , Macchini Elisabetta , Aune Vibeke , Drægni Tomas , Jacobsen Simon , Pieschke Søren , Rasmussen Åse , Akselsen Gro Ringstad , Langeland Halvor , Bergum Daniel , Erbe Therese M , Klepstad Pål , Næss Helle M , Olsen Roy Bjørkholt , Skjelnes Lena Eriksen , Holen Marius , Post Joakim Iver , Fanebust Rune , Sørensen Linda Hårteig , Kårstad Ken Åge , Wickman CarstenFredrik , Barnes Colin , Barry Ben , Beehre Nina , Dinsdale Dick , Edney Sam , Hunt Anna , Judd Harriet , Latimer-Bell Charlotte , Lawrence Cassie , Moore James , Olatunji Shaanti , Psirides Alex , Robinson Chelsea , Tietjens Kate , Wright Jason , Knight David , Birker Brandon , Bowie David , Burke Tara , Closey David , Crombie Rosalind , Davidson Neil , Henderson Seton , Hitchings Louise , McKay James , Mehrtens Jan , Minto Emmeline , Morgan Stacey , Morris Anna , Ritzemar-Carter Jay , Roberts Jessica , Shaw Geoffrey , Townend Katherine , Heyden Kymbalee Vander , Ahlqvist Marita , Lindgren Roman Desta , Eiving Ingrid , Martner Patrik , Myhrman Elisabeth , Ryding Birgitta , Düring Joachim , Bergström Mattias , Bohm Mattias , Didriksson Ingrid , Frid Petrea , Heimburg Katarina , Larsson Marina , Lundberg Oscar , Hau Stefan Olsson , Schmidbauer Simon , Borgquist Ola , Adolfsson Anne , Bjärnroos Anna , Blennow-Nordström Erik , Dragancea Irina , Kander Thomas , Lybeck Anna , Mattiasson Gustav , Persson Olof , Rundgren Malin , Schrey Susann , Westhall Erik , Annborn Martin , Andertun Sara , Gustavsson Nerida , Hassel Lisa , Johnsson Jesper , Nelderup Marie , Petersson Heléne , Petersson Jörgen , Stafilidou Frideriki , Undén Johan , Antonsson Frida , Bergman Git , Gamroth Jörgen , Meirik Maria , Rudolfsson Katarina , Sandberg Helena , Thorsson Martin , Savolainen Kristin , Hansbo Maria , Helliksson Malin , Nödtveidt Björne , Sanner Johan , Sem Victoria , Lindquist Camilla Sund , Awad Akil , Börjesson Anna-Sofia , Hedberg Malin , Henning Mia , Petersen Per , Dahlberg Emelia , Forshammar Johan , Svensson Veronica , Wanecek Michael , Eskilsson Håkan , Rodriguez-Santos Daniel , Appelqvist Åsa , Jidbratt Henrietta , Johansson Elisabeth , Kiszakiewicz Lars , Nilsson Åsa , Olsson Sinnika , Paulsson Anders , Stempel Urszula , Thoren Andreas , Persson Stefan , Berglund Ida , Bergström Eric , Törnqvist Cathrine , Östman Ingela , Rubertsson Sten , Larsson Ing-Marie , Söderman Elin , Wallin Ewa , Wessbergh Joanna , Halliday Thomas , Engvall Filippa , Ben-Hamouda Nawfel , Bernini Adriano , Carron Pierre-Nicolas , Eckert Philippe , Favre Eva , Miroz John-Paul , Morelli Paola , Muller Olivier , Novi Jan , Rosseti Andrea , Schnorf Madeleine , Haenggi Matthias , Levis Anja , Nansoz Sandra , Roth & Team Marianne , Söll Nicole , Schrag Claudia , Alicajic Mensur , Baier Philipp , Dütschler Joel , Flügel Dominique , Fässler Edith , Gamio-Veis Ruth , Güpfert Marc , Hilpertshauser Yvonne , Hägele-Link Stefan , Kleger Gian-Reto , Krähenmann Peter , Mair Maria Elisabeth , Schai Nadja , Strohmaier Christoph , Tangl Peter , Zieglgänsberger Dominik , Maggiorini Marco , Claus Gabriele , Consani-Vogel Gabi , Imbach Lukas , Kaiser Samira , Kleinert Eva-Maria , Garcia Pedro David Wendel , Cassina Tiziano , Agazzi Pamela , Capelli Bruno , Casso Gabriele , Regazzi Martino , Schlotterbeck Hervé , Via Gabriele , Villa Michele , Brooks Jenny , Cocks Eve , Cole Jade , Curtin Jacqueline , Davies Michelle , Davies Rhys , Fernandez Stephen , Highfield Julie , Hill Helen , Pennant Lydia , Rose Sofia , Thomas Emma , Williams Angharad , McGuigan Peter , Haffey Stephen , O’Neill Aisling , Ward Kathryn , Bewley Jeremy , Chillingworth Anna , Cloake Julie , Cole Libby , Galvin Hilary , Garland Zoe , Grimmer Lisa , Gumbrill Bethany , Howie Lucy , Johnson Rebekah , Searles Chloe , Skorko Agnieszka , Sweet Katie , Taylor Victoria , Webster Denise , Keeble Thomas , Adams Gill , Aggarwal Rajesh K. , Cartwright Jo-Anne , Church Steven , Clesham Gerald J. , Davies John R. , Farrell Kelly , Gamma Reto , Harding Jane , Jagathesan Rohan , Kabir Alamgir , Kelly Paul A. , Kittridge Lauren , Maccaroni Maria , Maloney Gracie , Mion Marco , Nain Naveen , Nalgirkar Raghunath , Namjoshi Gyanesh , Pepper Stacey , Redman Emily , Sayer Jeremy , Solesbury Amanda , Tang Kare H. , Urovi Sali , Waghmare Kunal , Watson Noel , Webber Teresa , Isherwood Peter , Bentley Conor , Bergin Colin , Carrera Ronald , Clark Amy , Cooper Lauren , Despy Liesl , Dooley Natalie , Ellis Karen , Fellows Emma , Goundry Stephanie , Harkett Samantha , McGhee Christopher , Neal Aoife , Smith Hazel , Snelson Catherine , Spruce Elaine , Whitehouse Tony , Yakoub Kamal , Walden Andrew , Bartley Shauna , Bhuie Parminder , Frise Matthew , Jacques Nicola , Keating Liza , Pogson David , Daly Zoe , Rose Steve , Bannard-Smith Jonathan , Quayle Rachael , Chee Nigel , Barratt Nina , Bowman Katie , Branney Debbie , Howe Elizabeth , Letts Maria , Pitts Sally , Vamplew Luke , Callaway Clifton W. , Sprouse Sara Difiore , Doshi Ankur A. , Fugate Jennifer , Headlee Amy M. , Wijdicks Eelco F. M. 
Published: October 2022

Abstract
Background
Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients’ outcome.

Methods
Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months.

Results
1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003).

Conclusions
In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients.
Trial registration: clinicaltrials.gov NCT02908308, Registered September 20, 2016.