title: Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).
abstract: In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested.
  
  
  
  In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients.
  
  
  
  We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31).
  
  
  
  In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: glenn.eastwood@austin.org.au.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Eastwood
authors.affiliation: Service de Médecine Intensive Adult Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Electronic address: Antoine.Schneider@chuv.ch.
authors.forename: Antoine G
authors.initials: AG
authors.lastname: Schneider
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Hospital, Okayama, Japan. Electronic address: Suzuki-s@mtc.biglobe.ne.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: leah.peck@austin.org.au.
authors.forename: Leah
authors.initials: L
authors.lastname: Peck
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: helen.young@austin.org.au.
authors.forename: Helen
authors.initials: H
authors.lastname: Young
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: aiko.tanaka@austin.org.au.
authors.forename: Aiko
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: johan.martensson@austin.org.au.
authors.forename: Johan
authors.initials: J
authors.lastname: Mårtensson
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: stephen.warrillow@austin.org.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Warrillow
authors.affiliation: Cardiothoracic and Vascular Intensive Care Unit Auckland City Hospital, Auckland, New Zealand. Electronic address: ShayMc@adhb.govt.nz.
authors.forename: Shay
authors.initials: S
authors.lastname: McGuinness
authors.affiliation: Cardiothoracic and Vascular Intensive Care Unit Auckland City Hospital, Auckland, New Zealand. Electronic address: RParke@adhb.govt.nz.
authors.forename: Rachael
authors.initials: R
authors.lastname: Parke
authors.affiliation: Cardiothoracic and Vascular Intensive Care Unit Auckland City Hospital, Auckland, New Zealand. Electronic address: EGilder@adhb.govt.nz.
authors.forename: Eileen
authors.initials: E
authors.lastname: Gilder
authors.affiliation: Cardiothoracic and Vascular Intensive Care Unit Auckland City Hospital, Auckland, New Zealand. Electronic address: LianneM@adhb.govt.nz.
authors.forename: Lianne
authors.initials: L
authors.lastname: Mccarthy
authors.affiliation: Department of Intensive Care Monash Medical Centre, Victoria, Australia. Electronic address: Pauline.Galt@monashhealth.org.
authors.forename: Pauline
authors.initials: P
authors.lastname: Galt
authors.affiliation: Department of Intensive Care Monash Medical Centre, Victoria, Australia. Electronic address: Gopal.Taoiri@monashhealth.org.
authors.forename: Gopal
authors.initials: G
authors.lastname: Taori
authors.affiliation: Department of Intensive Care Monash Medical Centre, Victoria, Australia. Electronic address: Suzanne.Eliott@monashhealth.org.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eliott
authors.affiliation: Department of Intensive Care Eastern Health, Victoria, Australia. Electronic address: tammy.lamac@easternhealth.org.au.
authors.forename: Tammy
authors.initials: T
authors.lastname: Lamac
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. Electronic address: michael.bailey@monash.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Department of Intensive Care Royal Melbourne Hospital, Victoria, Australia. Electronic address: Nerina.harley@rmh.org.au.
authors.forename: Nerina
authors.initials: N
authors.lastname: Harley
authors.affiliation: Department of Intensive Care Royal Melbourne Hospital, Victoria, Australia. Electronic address: Deborah.barge@mh.org.au.
authors.forename: Deborah
authors.initials: D
authors.lastname: Barge
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University Physiotherapy Department, The Alfred Hospital, Melbourne, Australia. Electronic address: carol.hodgson@monash.edu.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Hodgson
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia; Barrow Neurological Institute at Phoenix Children's Hospital, and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ, USA. Electronic address: Cristina.morganti-kossmann@monash.edu.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Morganti-Kossmann
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia. Electronic address: bay@unimelb.edu.au.
authors.forename: Alice
authors.initials: A
authors.lastname: Pébay
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia. Electronic address: alison.conquest@unimelb.edu.au.
authors.forename: Alison
authors.initials: A
authors.lastname: Conquest
authors.affiliation: Department of Medicine The University of Melbourne, Victoria, Australia. Electronic address: jarcher@unimelb.edu.au.
authors.forename: John S
authors.initials: JS
authors.lastname: Archer
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. Electronic address: S.Bernard@alfred.org.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bernard
authors.affiliation: Department of Cardiology, Alfred Hospital, Victoria, Australia. Electronic address: d.stub@alfred.org.au.
authors.forename: Dion
authors.initials: D
authors.lastname: Stub
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: graeme.hart@austin.org.au.
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Hart
authors.affiliation: Department of Intensive Care Austin Hospital, Victoria, Australia. Electronic address: rinaldo.bellomo@austin.org.au.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
mesh_terms: D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D005260:Female; D015600:Glasgow Coma Scale; D006323:Heart Arrest / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D006935:Hypercapnia; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000097:blood*; D012121:Respiration, Artificial / Q000379:methods*; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood*
chemical_list: D015415:Biomarkers; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; D010751:Phosphopyruvate Hydratase
keywords: Carbon dioxide; Cardiac arrest; Hypercapnia; Intensive care; Mechanical ventilation; Mortality