Clinical trial NCT03138005: Reduction of Oxygen After Cardiac Arrest
Official title: Reduction of Oxygen After Cardiac Arrest (EXACT): The EXACT Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Out-of-Hospital Cardiac Arrest
Keywords: Emergency Care, Prehospital
Resuscitation
Oxygen
Cardiac Arrest
Heart Arrest
Lead sponsor: Monash University
Sponsor class: OTHER
Collaborators: name: Ambulance Victoria
name: SA Ambulance Service
name: St John Ambulance Australia (Western Australia)
name: Flinders University
name: Curtin University
First posted: 2017-05-03
Enrollment: 1416
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Reduction of oxygen after cardiac arrest (EXACT) is a multi-centre, randomised, controlled trial (RCT) to determine whether reducing oxygen administration to target an oxygen saturation of 90-94%, compared to 98-100%, as soon as possible following successful resuscitation from OHCA improves outcome at hospital discharge.

Detailed description: Currently out-of-hospital cardiac arrest (OHCA) patients who achieve ROSC are routinely ventilated with the highest fraction of inspired oxygen (FiO2) possible (i.e. FiO2 1.0 or 100% oxygen) until admission to an intensive care unit (ICU) - usually a period of 2 to 6 hours post-ROSC.

Post-ROSC oxygen therapy begins in the field by emergency medical services (EMS). EMS typically deliver a high flow of oxygen at rate of \>10L/min (\~100% oxygen), and use a pulse oximeter to monitor oxygen levels (SpO2). Normal SpO2 levels are considered to be 94% to 100%. The delivery of 100% oxygen is then usually continued throughout a patient's stay in the emergency department (ED) and during any diagnostic testing (e.g. computed tomography scans and cardiac angiography). During this time, oxygen is delivered to patients who remain unconscious via a mechanical ventilator, with levels continuously monitored by pulse oximetry and periodically by a blood test called an arterial blood gas (ABG). The ABG measurements include the oxygen pressure in the blood (PaO2) in mmHg. Once a patient is admitted to the ICU, the PaO2 is assessed and the oxygen fraction is typically reduced and then titrated (reduced or increased) on the ventilator to achieve a normal level of PaO2 ("normoxia") of between 80-100mmHg.

The administration of 100% oxygen for the first hours after resuscitation is based largely on convention and not on any supportive clinical data. It has been thought that maximizing oxygen delivery for several hours might be beneficial in a patient who has suffered profound deprivation of oxygen supply ("hypoxia") during a cardiac arrest. In addition, if a lower fraction of inspired oxygen is delivered, there is a perceived risk that the patient might become hypoxic (i.e. SpO2 \<90% or PaO2 \<80mmHg). Until recently, there has been no particular reason to recommend a decrease in oxygen delivery to the post-arrest patient prior to admission to ICU.

However, recent systematic reviews of compelling experimental data and supportive human observational studies indicate that the administration of 100% oxygen can create "hyperoxic" levels in the early post arrest period which may lead to additional neurological injury, and thus result in worse clinical outcome. No randomised control trials have yet tested titrating oxygen administration to lower but normal levels (i.e. "normoxia").

EXACT is a Phase 3 multi-centre, randomised, controlled trial (RCT) aiming to determine whether reducing oxygen administration to target an oxygen saturation of 90-94%, compared to 98-100%, as soon as possible following successful resuscitation from OHCA improves outcome at hospital discharge.

Eligibility criteria: Inclusion Criteria:

* Adults (age 18 years or older)
* Out-of-hospital cardiac arrest of presumed cardiac cause
* All cardiac arrest rhythms
* Unconscious (Glasgow Coma Scale \<9)
* Return of spontaneous circulation
* Pulse oximeter measures oxygen saturation at ≥95% with oxygen flow set at \>10L/min or FiO2 at 100%
* Patient has an endotracheal tube (ETT) or supraglottic airway (SGA) (e.g. laryngeal mask airway -LMA) and is spontaneously breathing or ventilated
* Transport is planned to a participating hospital

Exclusion Criteria:

* Female who is known or suspected to be pregnant
* Dependent on others for activities of daily living (i.e. facilitated care or nursing home residents)
* "Not for Resuscitation" order or Advanced Care Directives in place
* Pre-existing oxygen therapy (i.e. for COPD)
* Cardiac arrest due to drowning, trauma or hanging

Primary outcomes:
measure: Survival to hospital discharge
timeFrame: At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
Secondary outcomes:
measure: Neurological outcome
timeFrame: At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
measure: Incidence of hypoxia (SpO2<90%)
timeFrame: Before ICU admission, an expected average of 4-6 hours
measure: Recurrent cardiac arrest
timeFrame: Before ICU admission, an expected average of 4-6 hours
measure: Myocardial Injury
timeFrame: First 24 hours of hospital admission
measure: Survival to intensive care unit discharge
timeFrame: Intensive care discharge, an expected average of 7 days
measure: Length of ICU stay
timeFrame: Intensive care discharge, an expected average of 7 days
measure: Length of hospital stay
timeFrame: At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
measure: Cause of death during hospital stay
timeFrame: At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
measure: Quality of Life SF-12
timeFrame: 12 months
measure: Quality of Life EQ-5D-3L
timeFrame: 12 months
measure: Neurological Function
timeFrame: 12 months
measure: Degree of recovery (GOS-E)
timeFrame: 12 months
measure: Survival at 12 months
timeFrame: 12 months
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Adelaide
country: Australia
facility: SA Ambulance Service
state: South Australia
city: Adelaide
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Western Health: Footscray Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Western Health: Sunshine Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: St Vincents Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Northern Health: The Northern Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Ambulance Victoria
state: Victoria
city: Melbourne
country: Australia
facility: Eastern Health: Maroondah Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Melbourne
country: Australia
facility: Peninusla Health: Frankston Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Barwon Health: Geelong
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: St John Ambulance Western Australia
state: Western Australia
Study officials:
affiliation: Ambulance Victoria
name: Stephen Bernard
role: PRINCIPAL_INVESTIGATOR
References:
citation: http://www.ambulance.vic.gov.au/Media/docs/VACAR-Annual-Report-201112-39a60ff4-083f-4893-af52-efeef570f6d1-0.pdf
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citation: Kilgannon JH, Jones AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, Parrillo JE, Trzeciak S; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA. 2010 Jun 2;303(21):2165-71. doi: 10.1001/jama.2010.707.
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citation: Ihle JF, Bernard S, Bailey MJ, Pilcher DV, Smith K, Scheinkestel CD. Hyperoxia in the intensive care unit and outcome after out-of-hospital ventricular fibrillation cardiac arrest. Crit Care Resusc. 2013 Sep;15(3):186-90.
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citation: Kuisma M, Boyd J, Voipio V, Alaspaa A, Roine RO, Rosenberg P. Comparison of 30 and the 100% inspired oxygen concentrations during early post-resuscitation period: a randomised controlled pilot study. Resuscitation. 2006 May;69(2):199-206. doi: 10.1016/j.resuscitation.2005.08.010. Epub 2006 Feb 24.
citation: Young P, Bailey M, Bellomo R, Bernard S, Dicker B, Freebairn R, Henderson S, Mackle D, McArthur C, McGuinness S, Smith T, Swain A, Weatherall M, Beasley R. HyperOxic Therapy OR NormOxic Therapy after out-of-hospital cardiac arrest (HOT OR NOT): a randomised controlled feasibility trial. Resuscitation. 2014 Dec;85(12):1686-91. doi: 10.1016/j.resuscitation.2014.09.011. Epub 2014 Sep 28.
citation: Young P, Pilcher J, Patel M, Cameron L, Braithwaite I, Weatherall M, Beasley R. Delivery of titrated oxygen via a self-inflating resuscitation bag. Resuscitation. 2013 Mar;84(3):391-4. doi: 10.1016/j.resuscitation.2012.08.330. Epub 2012 Sep 3.
citation: Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, Kelly AM, Silvester W; Rapid Infusion of Cold Hartmanns Investigators. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest*. Crit Care Med. 2012 Mar;40(3):747-53. doi: 10.1097/CCM.0b013e3182377038.
citation: Smith K, Andrew E, Lijovic M, Nehme Z, Bernard S. Quality of life and functional outcomes 12 months after out-of-hospital cardiac arrest. Circulation. 2015 Jan 13;131(2):174-81. doi: 10.1161/CIRCULATIONAHA.114.011200. Epub 2014 Oct 29.
citation: Kenmure AC, Murdoch WR, Beattie AD, Marshall JC, Cameron AJ. Circulatory and metabolic effects of oxygen in myocardial infarction. Br Med J. 1968 Nov 9;4(5627):360-4. doi: 10.1136/bmj.4.5627.360.
citation: Mak S, Azevedo ER, Liu PP, Newton GE. Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure. Chest. 2001 Aug;120(2):467-73. doi: 10.1378/chest.120.2.467.
citation: Nehme Z, Bernard S, Cameron P, Bray JE, Meredith IT, Lijovic M, Smith K. Using a cardiac arrest registry to measure the quality of emergency medical service care: decade of findings from the Victorian Ambulance Cardiac Arrest Registry. Circ Cardiovasc Qual Outcomes. 2015 Jan;8(1):56-66. doi: 10.1161/CIRCOUTCOMES.114.001185.
citation: O'Driscoll BR, Howard LS, Davison AG; British Thoracic Society. BTS guideline for emergency oxygen use in adult patients. Thorax. 2008 Oct;63 Suppl 6:vi1-68. doi: 10.1136/thx.2008.102947. No abstract available.
citation: Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation. 2011 Apr 5;123(13):1428-35. doi: 10.1161/CIRCULATIONAHA.110.988725. No abstract available.
citation: Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2;122(18 Suppl 3):S729-67. doi: 10.1161/CIRCULATIONAHA.110.970988.
citation: Soar J, Callaway CW, Aibiki M, Bottiger BW, Brooks SC, Deakin CD, Donnino MW, Drajer S, Kloeck W, Morley PT, Morrison LJ, Neumar RW, Nicholson TC, Nolan JP, Okada K, O'Neil BJ, Paiva EF, Parr MJ, Wang TL, Witt J; Advanced Life Support Chapter Collaborators. Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015 Oct;95:e71-120. doi: 10.1016/j.resuscitation.2015.07.042. Epub 2015 Oct 15. No abstract available.
citation: Bernard SA, Bray JE, Smith K, Stephenson M, Finn J, Grantham H, Hein C, Masters S, Stub D, Perkins GD, Dodge N, Martin C, Hopkins S, Cameron P; EXACT Investigators. Effect of Lower vs Higher Oxygen Saturation Targets on Survival to Hospital Discharge Among Patients Resuscitated After Out-of-Hospital Cardiac Arrest: The EXACT Randomized Clinical Trial. JAMA. 2022 Nov 8;328(18):1818-1826. doi: 10.1001/jama.2022.17701.
citation: Bray JE, Smith K, Hein C, Finn J, Stephenson M, Cameron P, Stub D, Perkins GD, Grantham H, Bailey P, Brink D, Dodge N, Bernard S; EXACT investigators. The EXACT protocol: A multi-centre, single-blind, randomised, parallel-group, controlled trial to determine whether early oxygen titration improves survival to hospital discharge in adult OHCA patients. Resuscitation. 2019 Jun;139:208-213. doi: 10.1016/j.resuscitation.2019.04.023. Epub 2019 Apr 19.