Key PointsQuestion
Among patients with return of spontaneous circulation after out-of-hospital cardiac arrest, does targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the intensive care unit improve survival?
Findings
In this randomized clinical trial that included 425 patients and was stopped early due to the COVID-19 pandemic, targeting an oxygen saturation of 90% to 94%, compared with an oxygen saturation of 98% to 100%, did not significantly improve survival to hospital discharge (rates of survival to hospital discharge, 38.3% vs 47.9%).
Meaning
The findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.
Importance
The administration of a high fraction of oxygen following return of spontaneous circulation in out-of-hospital cardiac arrest may increase reperfusion brain injury.
Objective
To determine whether targeting a lower oxygen saturation in the early phase of postresuscitation care for out-of-hospital cardiac arrest improves survival at hospital discharge.
Design, Setting, and Participants
This multicenter, parallel-group, randomized clinical trial included unconscious adults with return of spontaneous circulation and a peripheral oxygen saturation (Spo2) of at least 95% while receiving 100% oxygen. The trial was conducted in 2 emergency medical services and 15 hospitals in Victoria and South Australia, Australia, between December 11, 2017, and August 11, 2020, with data collection from ambulance and hospital medical records (final follow-up date, August 25, 2021). The trial enrolled 428 of a planned 1416 patients.
Interventions
Patients were randomized by paramedics to receive oxygen titration to achieve an oxygen saturation of either 90% to 94% (intervention; n = 216) or 98% to 100% (standard care; n = 212) until arrival in the intensive care unit.
Main Outcomes and Measures
The primary outcome was survival to hospital discharge. There were 9 secondary outcomes collected, including hypoxic episodes (Spo2 <90%) and prespecified serious adverse events, which included hypoxia with rearrest.
Results
The trial was stopped early due to the COVID-19 pandemic. Of the 428 patients who were randomized, 425 were included in the primary analysis (median age, 65.5 years; 100 [23.5%] women) and all completed the trial. Overall, 82 of 214 patients (38.3%) in the intervention group survived to hospital discharge compared with 101 of 211 (47.9%) in the standard care group (difference, −9.6% [95% CI, −18.9% to −0.2%]; unadjusted odds ratio, 0.68 [95% CI, 0.46-1.00]; P = .05). Of the 9 prespecified secondary outcomes collected during hospital stay, 8 showed no significant difference. A hypoxic episode prior to intensive care was observed in 31.3% (n = 67) of participants in the intervention group and 16.1% (n = 34) in the standard care group (difference, 15.2% [95% CI, 7.2%-23.1%]; OR, 2.37 [95% CI, 1.49-3.79]; P < .001).
Conclusions and Relevance
Among patients achieving return of spontaneous circulation after out-of-hospital cardiac arrest, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the intensive care unit did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.
Trial Registration
ClinicalTrials.gov Identifier: NCT03138005
Determination of an optimal postarrest oxygen target is a recognized gap in existing knowledge.1 Based on data from Australia from 2014 to 2016, the majority of patients with out-of-hospital cardiac arrest (OHCA) who achieve return of spontaneous circulation (ROSC) remain in a comatose state and require assisted ventilation during transport to the hospital (approximately 80%).2 Standard out-of-hospital practice is to provide a fraction of inspired oxygen (Fio2) of 100% until arrival at the emergency department, where the Fio2 is adjusted according to local mechanical ventilation and postarrest care protocols.
However, animal data3 and clinical studies4,5 have indicated that the administration of 100% oxygen during the early postarrest period may cause hyperoxia and associated neurological injury and less favorable clinical outcomes. The mechanism of harm of hyperoxia is thought to be related to an increase in the production of oxygen free radical molecules that are known to injure neurons (reperfusion injury).6 Supplemental oxygen may also cause additional injury to the myocardium in patients with coronary artery occlusion.7 Titration of oxygen in the out-of-hospital setting is feasible8; however, the efficacy and safety of this approach are uncertain.9
The Reduction of Oxygen After Cardiac Arrest (EXACT) trial was conducted to determine whether reducing oxygen fraction following resuscitation from OHCA in the out-of-hospital setting to target a peripheral oxygen saturation (Spo2) of 90% to 94%, compared with a target of 98% to 100%, improves survival at hospital discharge.
The EXACT trial was an investigator-initiated, multicenter, parallel-group, randomized clinical trial with patients, statistician, and 12-month outcome assessors blinded to treatment randomization.10 The study was conducted in 2 emergency medical services (EMS) and 15 hospitals in 2 Australian states. The protocol (Supplement 1), developed by the study steering committee, was approved by human research ethics committees at each hospital. The statistical analysis plan was developed by a statistician and the study steering committee (Supplement 2). Differences between the trial protocol, statistical analysis plan, and this report are described in eAppendix 1 in Supplement 3. An independent data and safety monitoring committee periodically reviewed blinded efficacy and safety data, with the option to request unblinded data if required. In Victoria, patients were enrolled under a waiver of consent, with survivors or surrogates notified of enrollment with the option to opt-out of data collection. In South Australia, patients were enrolled under a waiver of consent, with consent received for all patients who survived. The EMS and relevant practices are described in eAppendix 2 in Supplement 3 and resuscitation treatment followed the Australian Resuscitation Guidelines.11
Patients with ROSC following OHCA of presumed cardiac cause were eligible. Inclusion criteria were age 18 years or older, unconscious after ROSC, advanced airway (endotracheal tube or supraglottic airway), Spo2 of at least 95% while receiving more than 10 L/min of oxygen or Fio2 of 100%, and transport planned to a participating hospital. Paramedics determined the presumed cause at the time of enrollment, and patients with no other obvious cause of arrest were presumed to be of cardiac etiology.12,13
Patients were excluded if, at the time of enrollment, they had an obvious noncardiac cause of arrest (ie, respiratory, trauma, hanging, drowning), were known to or suspected of being pregnant, were dependent on others for activities of daily living or had a do-not-resuscitate order, or were receiving home oxygen therapy.
Patients were screened and randomized by paramedics trained in the study protocol. Patients were randomized in a 1:1 ratio to have a targeted Spo2 of 90% to 94% (intervention) or 98% to 100% (standard care). Randomization was generated in blocks of 10 by a computer-generated code and stratified by EMS. Paramedic teams were provided with sequentially numbered blocks of 10 sealed opaque envelopes containing a card and an airway tag indicating treatment randomization.
In the intervention group, oxygen was initially reduced to 4 L/min via an oxygen reservoir bag (Fio2 of approximately 0.7), or an oxygen/air mix setting (Fio2 of approximately 0.6) if the patient was receiving mechanical ventilation, and then titrated to maintain an Spo2 of 90% to 94%. Patients randomized to receive standard care were administered high-flow oxygen (Fio2 of 100% if receiving mechanical ventilation or >10 L/min of oxygen via an oxygen reservoir bag) in the out-of-hospital setting and then underwent oxygen titration via a ventilator to maintain an Spo2 of 98% to 100% in the hospital. The intervention continued until the first arterial blood gas measurement in the intensive care unit (ICU). Titration to 100% oxygen was allowed for subsequent intubation or hypoxic events (Supplement 1). Treatment of patients after hospital arrival followed the hospital’s standard practices for OHCA management, and hospital clinicians were not blinded to treatment randomization.
Unblinded research staff collected data from EMS and hospital medical records. The 12-month outcomes were obtained using telephone interview of patients or their proxies by trained staff who were blinded to treatment randomization.
The primary outcome was survival to hospital discharge. Prespecified secondary outcomes collected prior to hospital discharge (Supplement 2 and eAppendix 1 in Supplement 3) were rates of rearrest and hypoxia (Spo2 <90%) before ICU admission, myocardial injury (peak troponin level), survival to ICU discharge, ICU and hospital length of stay, cause of in-hospital mortality, favorable neurological outcome (Cerebral Performance Category score of 1-2) at hospital discharge, and discharge destination (in survivors). The Cerebral Performance Category score is a 5-point scale measuring neurological outcomes following brain injury, ranging from good functioning (score of 1 to 2) to brain death (score of 5).14
Prespecified secondary outcomes measured at 12 months included survival and health-related quality of life. Measures used were the mental and physical components of the generic 12-Item Short Form Health Survey, with higher scores representing greater mental and physical health and scores greater than 50 representing no disability15; the EuroQol 5 Dimension 5 index, which indexes a person’s self-rated health, ranging from −0.59 to 1, with the lowest score indicating the worst imaginable health state and the highest indicating the best imaginable health state16; the Glasgow Outcome Scale-Extended, with scores categorized into good recovery (score of 1-2), moderate disability (score of 3-4), or severe disability to death (score of 5-8)17; and the modified Rankin Scale score, a 7-point scale measuring the degree of disability and dependence in daily living, with favorable outcomes considered to be scores of 0 to 2 (no or minimal disability) and unfavorable outcomes defined as scores of 3 to 5 (significant disability) or 6 (death).18
The predefined serious adverse events were sustained hypoxia (Spo2 <90%), unresponsive to 100% oxygen, and rearrest in the setting of hypoxia (Spo2 <90%).
The study was planned to enroll 1416 patients, which would have allowed 90% power to determine a relative difference of 25% between the groups for the primary outcome. The standard care group was expected to have a 35% survival rate at hospital discharge19 and the intervention group was anticipated to have a 44% survival rate. The effect size was based on a large observational clinical study20 and 2 meta-analyses of observational studies.21,22 After adjusting for the interim analysis, the study would have required 643 patients per group with 90% power and restricted α = .049, with 10% added to this sample size to account for loss to follow-up.
Groups were analyzed according to randomization group, excluding patients who did not consent (South Australia only) or requested data be withdrawn. A secondary prespecified analysis of all outcomes was performed excluding patients enrolled with known exclusion criteria.
As a result of the early cessation of the study, the statistical plan was adjusted prior to database lock to remove the statistical comparison for 12-month outcomes and to include a multivariable analysis of the primary outcome as a supplementary analysis (Supplement 2 and eAppendix 1 in Supplement 3). Primary and secondary outcomes were analyzed by a statistician blinded to treatment randomization, and all data related to oxygenation were withheld until that analysis was complete.
Binary and categorical variables are expressed as proportions and percentages and continuous data are summarized as mean and SD or as median and IQR as appropriate. Per the published protocol,10 the analysis of the primary outcome and other binary or categorical outcomes was tested using χ2 tests. Estimates and their 95% CIs were determined using logistic regression. Normally distributed data were tested using t tests and nonnormal continuous data were analyzed using Wilcoxon rank sum tests, except for length of stay outcomes, for which median regression was performed. There was no imputation performed for other missing data.
Planned subgroup analyses for the primary outcome were assessed with the use of regression models with tests for the interactions between the subgroup and the randomized group. Per the statistical analysis plan, subgroups included were age (<65 y), sex, witnessed arrest, bystander cardiopulmonary resuscitation (CPR), shockable rhythm, time from collapse to ROSC, and ST-segment elevation myocardial infarction. Due to small numbers and data collection, 2 additional prespecified subgroups were not analyzed (eAppendix 1 in Supplement 3).
Exploratory post hoc analyses are detailed in eAppendix 1 in Supplement 3. This analysis included a multivariable logistic regression for survival to hospital discharge by treatment group, adjusting for known predictors of survival13 and hospital site using mixed-effects logistic regression. Additional post hoc analyses were performed to examine differences between treatment groups for survival to discharge stratified by the time from emergency call to randomization, the timing of withdrawal of life-sustaining treatment, and rates of hypoxia and rearrest without ROSC in the subgroup of patients who received bystander CPR.
Subgroup analyses and secondary end points were not adjusted for multiplicity. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary outcomes and subgroups should be interpreted as exploratory. Reported P values are 2-sided, with a P value of <.05 considered significant. The statistical software used was STATA, version 16.0 (Stata Corporation).
On August 7, 2020, the study steering committee discussed and approved ceasing the trial based on decreased trial enrollment and COVID-19 pandemic–related changes in OHCA protocols and survival rates.23 The ethics committees, paramedics, and site investigators were notified and the trial ceased on August 11, 2020, at which time 428 patients had been enrolled. This decision was made without knowledge of the outcomes of the study, per the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) 2021 statement.24 Similar numbers of unused randomization envelopes were accounted for in each study group (47% in the intervention group and 49% in standard care group).
Between December 11, 2017, and August 11, 2020, a total of 425 of 428 patients were enrolled and included in the main analysis, with 214 randomized to the intervention group (titrated to maintain Spo2 of 90%-94%) and 211 randomized to the standard care group (titrated to maintain Spo2 of 98%-100%) (Figure 1). Three patients who were randomized were not included in the main analyses (consent was not received for 2 and data withdrawal requested for 1). There were 32 ineligible patients randomized (18 in the intervention group and 14 in the standard care group; eTable 1 in Supplement 3). Follow-up at hospital discharge was complete for all patients.
The baseline data were similar between the 2 groups (Table 1). The median (IQR) age was 65.5 (53.1-76.4) years and 100 patients (23.5%) were women. Most arrests were bystander-witnessed (74.5%), most individuals received bystander CPR (81.0% of bystander-witnessed arrests), and most were initially in a shockable cardiac rhythm (62.0%).
The median (IQR) time from ROSC to randomization was 36 (23-46) minutes. Group comparisons for the pulse oximeter data for the 6 hours following randomization are shown in eFigure 1 in Supplement 3, time to first arterial blood gas measurement is shown in eTable 2 in Supplement 3, and oxygenation and oxygen delivery during the intervention period are shown in Table 2. These data show differences between groups for oxygenation and oxygen delivery in line with the trial protocol. For example, the median (IQR) last recorded Fio2 in the emergency department was 0.5 (0.4-0.8) in the intervention group and 0.8 (0.5-1.0) in the standard care group.
Other clinical measures and postarrest treatments are shown in Table 2. Similar rates for key elements of postresuscitation care were seen between the 2 groups, with 60.3% undergoing coronary angiography and 78.9% of those admitted to the ICU receiving targeted temperature control.
The number of patients who survived to hospital discharge was 82 of 214 (38.3%) in the intervention group compared with 101 of 211 (47.9%) in the standard care group (difference, −9.6% [95% CI, −18.9% to −0.2%]; odds ratio [OR], 0.68 [95% CI, 0.46-1.00]; P = .05) (Table 3). Survival to hospital discharge, in a sensitivity analysis restricted to eligible patients (n = 393), was not statistically different between groups (OR, 0.71 [95% CI, 0.48-1.06]; P = .09) (eTable 3 in Supplement 3).
Of the 9 prespecified secondary outcomes collected up to hospital discharge, 8 were not statistically significantly different between treatment groups. A hypoxic episode prior to intensive care was observed in 31.3% (n = 67) of participants in the intervention group and 16.1% (n = 34) in the standard care group (difference, 15.2% [95% CI, 7.2%-23.1%]; OR, 2.37 [95% CI, 1.49-3.79]; P < .001).
In patients surviving to hospital discharge, 147 of 183 (80.3%) were followed up at 12 months, with 141 consenting to 12-month quality of life questions, 6 deceased, and 19 lost to follow-up (5/82 in the intervention and 14/101 in the standard care group; eTable 4 in Supplement 3). Survival at 12 months was 35% (72/208) in the intervention group and 42% (81/193) in the standard care group. Quality of life scores for the treatment groups are reported in eTable 4 and eFigure 2 in Supplement 3.
A sustained hypoxic event (Spo2 <90%) unresponsive to 100% oxygen was seen in 5 participants (2.3%) in the intervention group and in 3 (1.4%) in the standard care group. All 3 patients (1.4%) who had rearrest in the setting of hypoxia (Spo2 <90%) were in the intervention group.
Results were consistent across 6 of the 7 prespecified subgroups (Figure 2). The association between treatment and survival varied according to whether the patient received bystander CPR (bystander CPR: OR, 0.48 [95% CI, 0.31-0.75]; no bystander CPR: OR, 1.96 [95% CI, 0.72-5.33]; interaction P = .01). A post hoc examination showed that those in the intervention group who received bystander cardiopulmonary resuscitation had higher rates of hypoxia (Spo2 < 90%; 30% vs 16%) and rearrest without ROSC (14% vs 4%) than those in the standard care group who received bystander CPR.
A post hoc analysis showed no significant difference in survival to discharge when adjusting for known predictors and site (OR, 0.61 [95% CI, 0.36, 1.03]; P = .06). There was no statistical difference between treatment groups for survival to discharge stratified by time from EMS call to randomization (eTable 5 in Supplement 3) or the early withdrawal of life support (<72 hours after randomization) (eTable 6 in Supplement 3).
Among patients achieving ROSC after OHCA, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the ICU did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.
The outcome in this study contrasts with previous findings of an association between hyperoxia during the early postarrest period and increased neurological injury in animal,3 neonate,25 and adult studies.4,5 An initial observational study in adult patients with cardiac arrest by Kilgannon et al20 reported that hyperoxia (first Pao2 in ICU ≥300 mm Hg), compared with normoxia (Pao2 between 60 and 299 mm Hg), was associated with significantly higher in-hospital mortality (63% vs 45%; difference, 18% [95% CI, 14%-22%]). However, Kilgannon et al20 used a single blood gas measurement. Other smaller observational studies in similar cohorts have found no significant difference in outcomes related to oxygen saturation.26,27
There have been several preliminary randomized clinical trials comparing titration of oxygen to different levels in the out-of-hospital8,28-30 and in-hospital31,32 settings in patients after cardiac arrest. An individual patient data meta-analysis of these trials indicated that conservative oxygen therapy was significantly associated with reduced mortality compared with liberal oxygen therapy.5 Although this meta-analysis mainly included patients with OHCA (406 of 429), it did not examine differences by the setting of oxygen titration.
The outcomes in the current study suggest possible harm in patients who underwent reduction of oxygen targeting a saturation of 90% to 94% commencing in the out-of-hospital setting. It is possible that the methods of titration used in the current trial resulted in relatively large decreases in the delivery of oxygen, which, in patients with decreased cerebral blood flow due to a low cardiac output, resulted in additional cerebral hypoxic injury. It is also possible that the increase in hypoxic events in the intervention group resulted in myocardial ischemia, which may explain the increased number of rearrests with no ROSC seen in this treatment group.
Titrating oxygen in the out-of-hospital setting is challenging when using the equipment available in this trial. The air-mix settings on the available ventilators did not allow for slow titration and, although titration of oxygen flow into the ventilation bag reservoir is feasible in a laboratory setting,33 it may be difficult to provide a reliable Fio2 in practice and this approach may result in increased episodes of oxygen desaturation.30 Therefore, it is suggested that future studies be performed in hemodynamically stable patients after hospital arrival with mechanical ventilators that provide a precise delivery of oxygen.
Additionally, it may be that a target oxygen saturation of 90% to 94% soon after ROSC is too low, noting the recent recommendations from the European Resuscitation Council and European Society of Intensive Care Medicine Guidelines of a target of an oxygen saturation of 94% to 98% during postarrest care.34
This study has several limitations. First, the number of patients enrolled was less than the planned enrollment. However, the decision to stop the study was made without the investigators being aware of study patient outcomes and prior to any analysis. Second, the methods of titration of oxygen, to either different oxygen flows to bags with reservoirs or EMS ventilators limited to either 100% oxygen or oxygen with air mix, did not allow for accurate oxygen titration. Third, most trial patients had an arrest of cardiac etiology and the findings may not be applicable to other etiologies. Fourth, as with many out-of-hospital studies, it was difficult to ensure that only eligible patients are enrolled and that the trial protocol was closely followed.
Among patients achieving ROSC after out-of-hospital cardiac arrest, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the ICU did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.
Corresponding Author: Stephen Bernard, MD, Ambulance Victoria, 375 Manningham Rd, Doncaster, Victoria 3108, Australia (stephen.bernard@ambulance.vic.gov.au).
Accepted for Publication: September 9, 2022.
Published Online: October 26, 2022. doi:10.1001/jama.2022.17701
Author Contributions: Drs Bernard and Bray had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Bernard and Bray contributed equally to this article as co–first authors.
Concept and design: Bernard, Bray, Smith, Stephenson, Finn, Grantham, Hein, Stub, Perkins, Cameron.
Acquisition, analysis, or interpretation of data: Bray, Smith, Stephenson, Grantham, Hein, Masters, Stub, Perkins, Dodge, Martin, Hopkins, Cameron.
Drafting of the manuscript: Bernard, Bray.
Critical revision of the manuscript for important intellectual content: Smith, Stephenson, Finn, Grantham, Hein, Masters, Stub, Perkins, Dodge, Martin, Hopkins, Cameron.
Statistical analysis: Martin.
Obtained funding: Bernard, Bray, Smith, Stephenson, Finn, Hein, Stub, Perkins, Cameron.
Administrative, technical, or material support: Bray, Smith, Stephenson, Grantham, Hein, Masters, Stub, Dodge, Hopkins, Cameron.
Supervision: Bernard, Bray, Smith, Stephenson, Perkins, Cameron.
Conflict of Interest Disclosures: None reported.
Funding/Support: The trial was funded by a project grant from the National Health and Medical Research Council (NHMRC; project grant number APP1107509). The Australasian Resuscitation Outcomes Consortium and the NHMRC Prehospital Emergency Care Centre of Research Excellence (number 116453) provided administrative support. Dr Finn receives an NHMRC investigator grant (number 1174838), Dr Cameron receives a Medical Research Future Fund fellowship (number 1139686), and Drs Bray and Stub receive Heart Foundation fellowships (numbers 104751/105793). Dr Perkins is supported by the National Institute for Health Research Applied Research Collaboration West Midlands. Drs Bernard, Bray, Smith, Stephenson, Finn, Grantham, Hein, Stub, Perkins, and Cameron received funding from the NHMRC.
Role of the Funder/Sponsor: The NHMRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: The EXACT Investigators appear in Supplement 4.
Disclaimer: The views expressed are those of the author(s) and not necessarily those of the National Institute for Health and Care Research or the Department of Health and Social Care.
Data Sharing Statement: See Supplement 5.
Meeting Presentation: This paper was presented at the European Society of Intensive Care Medicine meeting; October 26, 2022; Paris, France.
Additional Contributions: We thank the paramedics at Ambulance Victoria and SA Ambulance Service for their contribution in screening, enrolling, and treating study patients. We also thank members of the data and safety monitoring committee (Christopher Reid, PhD [Curtin University]; Laurent Billot, MSc [University of New South Wales]; and Ian Patrick, ASM [Monash University]); and Stuart Howell, PhD (Monash University), for providing data to this committee with compensation for this role.
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