Reduction of Oxygen After Cardiac Arrest

Out-of-Hospital Cardiac Arrest Clinical Trial

— EXACT  

Official title:

Reduction of Oxygen After Cardiac Arrest (EXACT): The EXACT Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03138005
• Other study ID #: EXACT01
• Secondary ID: APP1107509
• Status: Recruiting
• Phase: N/A
• Start date: December 11, 2017
• Est. completion date: December 2020

Study information

• Verified date: August 2020
• Source: Monash University
• Contact: Natasha Dodge
• Phone: +6139930039
• Email: SPHPM.EXACT.Study[@]monash.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1416
• Est. completion date: December 2020
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Arrest
• Out-of-Hospital Cardiac Arrest

Intervention

Other:
• target SpO2 98-100%
Prehospital, post-ROSC oxygen maintained at =10L/minute of oxygen (equivalent to ~100% oxygen) into SGA/ETT if hand ventilated or 100% (i.e. FiO2 of 1.0) oxygen settings if mechanically ventilated. Patients will continue on treatment to handover in the ED. Between arrival at ED and first ABG in ICU, the oxygen setting may then be decreased provided SpO2 is maintained between 98-100%.
• target SpO2 90-94%
Prehospital, post-ROSC oxygen reduced initially to 4L/minute (i.e. approximately 70% oxygen) into SGA/ETT if hand ventilated or an air mix setting if mechanically ventilated. If oxygen saturation remains =94% for 5 minutes, the oxygen flow rate will be further reduced to 2L/minute (i.e. approximately 46% oxygen) and hand ventilated to target an oxygen saturation between 90-94%. This treatment will continue to patient handover in the emergency department. Between arrival at ED and first ABG in ICU, oxygen will be titrated to target a oxygen saturation of 90-94%.

Locations

Country	Name	City	State
Australia	Lyell McEwin Hospital	Adelaide	South Australia
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	SA Ambulance Service	Adelaide	South Australia
Australia	The Queen Elizabeth Hospital	Adelaide	South Australia
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Ambulance Victoria	Melbourne	Victoria
Australia	Austin Hospital	Melbourne	Victoria
Australia	Barwon Health: Geelong	Melbourne	Victoria
Australia	Box Hill Hospital	Melbourne	Victoria
Australia	Eastern Health: Maroondah Hospital	Melbourne	Victoria
Australia	Monash Medical Centre	Melbourne	Victoria
Australia	Northern Health: The Northern Hospital	Melbourne	Victoria
Australia	Peninusla Health: Frankston Hospital	Melbourne	Victoria
Australia	St Vincents Hospital	Melbourne	Victoria
Australia	The Royal Melbourne Hospital	Melbourne	Victoria
Australia	Western Health: Footscray Hospital	Melbourne	Victoria
Australia	Western Health: Sunshine Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Perth	Western Australia
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Sir Charles Gairdner Hospital	Perth	Western Australia
Australia	St John Ambulance Western Australia	Perth	Western Australia

Sponsors (6)

Lead Sponsor	Collaborator
Monash University	Ambulance Victoria, Curtin University, Flinders University, SA Ambulance Service, St John Ambulance Australia (Western Australia)

Country where clinical trial is conducted

Australia, 

References & Publications (23)

Balan IS, Fiskum G, Hazelton J, Cotto-Cumba C, Rosenthal RE. Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest. Stroke. 2006 Dec;37(12):3008-13. Epub 2006 Oct 26. — View Citation

Bellomo R, Bailey M, Eastwood GM, Nichol A, Pilcher D, Hart GK, Reade MC, Egi M, Cooper DJ; Study of Oxygen in Critical Care (SOCC) Group. Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. Crit Care. 2011;15(2):R90. doi: 10.1186/cc10090. Epub 2011 Mar 8. — View 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. — View Citation

Hellström-Westas L, Forsblad K, Sjörs G, Saugstad OD, Björklund LJ, Marsál K, Källén K. Earlier Apgar score increase in severely depressed term infants cared for in Swedish level III units with 40% oxygen versus 100% oxygen resuscitation strategies: a population-based register study. Pediatrics. 2006 Dec;118(6):e1798-804. — View Citation

http://www.ambulance.vic.gov.au/Media/docs/VACAR-Annual-Report-201112-39a60ff4-083f-4893-af52-efeef570f6d1-0.pdf

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. — View Citation

Kaneda T, Ku K, Inoue T, Onoe M, Oku H. Postischemic reperfusion injury can be attenuated by oxygen tension control. Jpn Circ J. 2001 Mar;65(3):213-8. — View 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. — View 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. — View Citation

Kuisma M, Boyd J, Voipio V, Alaspää 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. Epub 2006 Feb 24. — View 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. — View 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. — View 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. Review. Erratum in: Circulation. 2011 Feb 15;123(6):e236. Circulation. 2013 Dec 24;128(25):e480. — View 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. Erratum in: Thorax. 2009 Jan;64(1):91. — View Citation

Pilcher J, Weatherall M, Shirtcliffe P, Bellomo R, Young P, Beasley R. The effect of hyperoxia following cardiac arrest - A systematic review and meta-analysis of animal trials. Resuscitation. 2012 Apr;83(4):417-22. doi: 10.1016/j.resuscitation.2011.12.021. Epub 2012 Jan 5. Review. — View Citation

Richards EM, Fiskum G, Rosenthal RE, Hopkins I, McKenna MC. Hyperoxic reperfusion after global ischemia decreases hippocampal energy metabolism. Stroke. 2007 May;38(5):1578-84. Epub 2007 Apr 5. — View Citation

Saugstad OD. Resuscitation of newborn infants: from oxygen to room air. Lancet. 2010 Dec 11;376(9757):1970-1. doi: 10.1016/S0140-6736(10)60543-0. Epub 2010 Jul 19. — View 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. — View Citation

Soar J, Callaway CW, Aibiki M, Böttiger 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. Review. — View 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. Review. — View Citation

Suzuki S, Eastwood GM, Glassford NJ, Peck L, Young H, Garcia-Alvarez M, Schneider AG, Bellomo R. Conservative oxygen therapy in mechanically ventilated patients: a pilot before-and-after trial. Crit Care Med. 2014 Jun;42(6):1414-22. doi: 10.1097/CCM.0000000000000219. — View 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. — View 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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival to hospital discharge	Survival to hospital discharge	At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
Secondary	Neurological outcome	Cerebral Performance Category score	At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
Secondary	Incidence of hypoxia (SpO2<90%)	Incidence of hypoxia (SpO2<90%)	Before ICU admission, an expected average of 4-6 hours
Secondary	Recurrent cardiac arrest	Recurrent cardiac arrest requiring chest compressions before admission to ICU and not related to withdrawal of life sustaining-treatment	Before ICU admission, an expected average of 4-6 hours
Secondary	Myocardial Injury	Median peak troponin	First 24 hours of hospital admission
Secondary	Survival to intensive care unit discharge	Survival to intensive care unit discharge	Intensive care discharge, an expected average of 7 days
Secondary	Length of ICU stay	Length of ICU stay	Intensive care discharge, an expected average of 7 days
Secondary	Length of hospital stay	Length of hospital stay	At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
Secondary	Cause of death during hospital stay	e.g. cardiogenic shock, re-arrest with no ROSC, treatment withdrawn -hypoxic brain injury, brain death	At hospital discharge, participants will be followed for the duration of hospital stay, an expected average of 2-4 weeks
Secondary	Quality of Life SF-12	The SF-12 Health Survey (SF-12) is a 12-item questionnaire used to assess health outcomes from the patient's perspective.	12 months
Secondary	Quality of Life EQ-5D-3L	Quality of life assessment using the EQ-5D-3L descriptive system that comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems.	12 months
Secondary	Neurological Function	Modified Rankin Score	12 months
Secondary	Degree of recovery (GOS-E)	Extended Glasgow Outcome Scale	12 months
Secondary	Survival at 12 months	Survival at 12 months	12 months