Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Importance  Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies.

Objective  To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI).

Design, Setting, and Participants  A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized.

Interventions  Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group).

Main Outcomes and Measures  The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months.

Results  Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053).

Conclusions and Relevance  Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest.

Trial Registration  clinicaltrials.gov Identifier: NCT00879892

Quiz Ref IDSurvivors of out-of-hospital cardiac arrest have a poor prognosis with high rates of death and the likelihood of having severe neurological problems.^1-5 International guidelines recommend the provision of therapeutic hypothermia for comatose survivors of out-of-hospital cardiac arrest; these guidelines are based on 2 studies^2,3 in which patients with an initial shockable rhythm who had been cooled to 33°C achieved a better clinical outcome. However, a recent study⁴ suggested that preventing hyperthermia through targeted temperature management to 36°C could be as neuroprotective as 33°C regardless of the initial rhythm at the time of the out-of-hospital cardiac arrest. The optimal temperature for targeted temperature management has yet to be defined and the efficacy of the treatment is modest at best.^2,3

Quiz Ref IDIn animal studies, the neuroprotective properties of the inhaled noble gas xenon have been established; these effects are mediated through multiple putative molecular targets in the pathways involved in postresuscitation brain injury.^6-12 Neuroprotection associated with xenon has been especially evident when combined with hypothermia (33°C to 35°C) and both additive and synergistic interactions have been reported on the basis of histopathological and functional outcomes.^9-12 A recent study¹³ demonstrated that xenon inhalation is well tolerated and has favorable cardiovascular properties when administered to patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest.

In this study, we investigated the effect of xenon on the extent of cerebral white matter brain damage as assessed by diffusion tensor magnetic resonance imaging (MRI) in comatose survivors from out-of-hospital cardiac arrest who have hypoxic-ischemic brain injury.

We conducted a randomized 2-group single-blind phase 2 clinical drug trial at 2 multipurpose intensive care units in Finland. The study was approved by the ethics committee of the Hospital District of Southwest Finland and the institutional review boards of the Helsinki University Hospital and the Finnish Medicines Agency. An independent data and safety monitoring committee reviewed data after enrollment of every 4 patients and after each 6-month interval.

The study was conducted according to good clinical practice and the current revision of the Declaration of Helsinki¹⁴ guiding clinical drug research in human subjects. Written informed assent was obtained from the next of kin or from the legal representative of the patient within 4 hours after hospital arrival. The patient’s family was informed about the right to withdraw from the study at any point but that the data collected until possible withdrawal could be used in the analyses as predefined in the trial protocol (Supplement 1). Patients were informed accordingly if they regained consciousness. The mode of death was classified as neurological, cardiological, or multiorgan as described earlier.¹

The patients were allocated in 1:1 ratio with random block sizes of 4, 6, and 8 to receive either therapeutic hypothermia treatment alone for 24 hours (defined as the control group) or inhaled xenon (LENOXe, Air Liquide Medical GmbH) in combination with hypothermia for 24 hours (defined as the xenon group). The treatment assignments were randomly generated by a computer. Sequentially numbered sealed envelopes were used separately in the 2 centers for randomization, which was performed after the assent was granted. Clinical investigators performed the patient enrollment, randomization, and intervention assignment. Personnel involved in the treatment of the patient could not be blinded due to practical and safety considerations; however, the MRI analysis of white matter injury was operator-independent, and the neurological end point evaluators as well as the patients were blinded to the treatment.

The diffusion tensor MRI results were not made available to the clinicians treating the patients to avoid bias. For patients in whom there was premature termination of the hypothermia treatment, xenon administration also was discontinued. A local neurological prognostication consensus was used in decisions to withdraw life-sustaining treatment (eMethods in Supplement 2).

Comatose survivors of out-of-hospital cardiac arrest consecutively admitted to the Turku and Helsinki University hospitals were screened for eligibility. The main criteria for inclusion were witnessed cardiac arrest from an initial rhythm amenable to defibrillation (ie, ventricular fibrillation or nonperfusing ventricular tachycardia and return of spontaneous circulation within ≤45 minutes). Details of inclusion and exclusion criteria appear in eTable 1 in Supplement 2.

The patients underwent coronary angiographic interventions when clinically indicated. Integrated care after cardiac arrest and patient monitoring adhered to recent recommendations.^2,15 There was adherence to the detailed treatment protocol regarding cooling treatment and xenon intervention (eMethods in Supplement 2). Inhaled xenon was initiated immediately after randomization through a closed-system ventilator (PhysioFlex, Dräger). Oxygen and air were delivered to achieve an end-tidal xenon concentration of at least 40% (measured continuously by the thermoconductive monitor on the ventilator).

The primary end point was the severity of ischemic white matter brain injury as evaluated by fractional anisotropy from diffusion tensor MRI. Although the study was not powered to detect statistical differences in clinical efficacy, the following variables were collected as exploratory secondary end points: neurological outcome using the Cerebral Performance Category (CPC) score (from 1 [conscious, alert, able to work, might have mild cognitive deficit] to 5 [death]) and the modified Rankin Scale (mRS) score (from 0 [no symptoms] to 6 [death]), mortality at 6 months, and the complication (eg, severe bleeding, pneumonia, sepsis, acute kidney injury,¹⁶ pulmonary edema, ventricular arrhythmias, and epileptic status¹⁷) rate within 7 days after cardiac arrest.

The Mini-Mental State Examination (MMSE) (score range, 0-30; ≥24 indicates no impairment) and the National Institutes of Health Stroke Scale (NIHSS) (score range, 0-42; higher scores indicate greater severity) were used to assess the 6-month exploratory neurocognitive outcome. The minimally clinically important differences for CPC and NIHSS have not been established; changes in MMSE of 4 or more points have been interpreted as clinically significant.¹⁸ Differences in mRS score as low as 0.46 have been considered clinically meaningful by practice guidelines.^19,20

Quiz Ref IDThe difference in the severity of white matter damage in the control and xenon groups was analyzed by comparing the values of global fractional anisotropy and diffusivity assessment (mean, axial, and radial) obtained from the diffusion tensor MRI. White matter damage evokes a loss of microstructural organization that can be quantified by the loss of directionality in the diffusion of water molecules in the white matter tracts. Fractional anisotropy is a scalar value representing this directionality of water diffusion; lower fractional anisotropy values are indicative of less organized diffusion and indicate more extensive white matter damage.²¹ Mean diffusivity values measure overall diffusion and mostly represent cellularity and membrane density; they are affected by several pathological processes (eg, edema and necrosis). Axial diffusivity values represent the amount of water diffusing along the principal axis of the diffusion ellipsoid, whereas radial diffusivity values depict diffusion perpendicular to the principal axis; these values reflect axonal injury and myelin loss, respectively.^22-24

Patients were scheduled to undergo brain MRI within 16 hours after rewarming; ranging from 36 to 52 hours after out-of-hospital cardiac arrest. Magnetic resonance imaging was performed with a Verio 3T scanner (Siemens Medical Solutions) at both centers, with identical imaging protocols. Diffusion tensor MRI data was preprocessed using DTIprep quality control software (eMethods in Supplement 2). Version 5.0 of the FSL software package (FMRIB) was used for the tract-based spatial statistical analysis.^25-29 This observer-independent and hypothesis-free method has the ability to spatially locate group differences in the diffusion tensor MRI data.

Fractional anisotropy and diffusivity maps were calculated for each patient and these images were projected on a mean skeleton with a voxel size of 1 × 1 × 1 mm (ie, 119 013 voxels per patient), which represents the centers of all major white matter structures. These skeletonized images were then used for voxel-wise statistics to identify all tracts with voxels revealing statistically significant differences in diffusion parameters. Localization and labeling of the major white matter tracts were confirmed according to the Johns Hopkins University white matter tractography atlas.³⁰ Additional details of the MRI protocol, quality control of imaging, image processing, and tract-based spatial statistics appear in the eMethods, eTable 2, and eTable3 in Supplement 2.

The sample size was based on a power analysis of fractional anisotropy values. However, a clinically relevant difference in the effect size had not been established. Therefore, this difference was arbitrarily set at 15%, which proved to be unrealistically large given that the difference in the mean fractional anisotropy values between those patients who survived and those who died was only 6.4% (eTable 7 in Supplement 2). The number of patients was predetermined based on the result obtained from the power analysis. Accordingly, it was estimated that 55 patients per group would be needed to reveal an absolute median difference of 15% in fractional anisotropy between the groups (85% power and a 2-sided α level of .05).

The Shapiro-Wilk W test was used to test for normality of all continuous variables. The 2-sample t test and the Mann-Whitney test were used to compare continuous variables between the groups. Categorical variables were analyzed with the χ² test or the Fisher exact test. The Mann-Whitney test and the Hodges-Lehmann estimate were used for the ordinal variables of mRS and CPC to calculate median differences between the groups. Between-group differences in global fractional anisotropy and diffusivity values (radial, axial, and mean) were analyzed using the 2-sample t test and analysis of covariance with adjustment for age, sex, and site as recommended.³¹ Permutation-based voxel-wise statistical analysis of fractional anisotropy values was performed with tract-based spatial statistics in conjunction with family-wise error correction for multiple comparisons across space.²⁹

The follow-up time for survival analysis was calculated from the time of cardiac arrest until death or 6 months. A complete case analysis was applied to the primary end point due to missing MRI data for 6 patients in the control group and 7 patients in the xenon group. Multiple imputation was not performed due to lack of a good prognostic model to predict valid imputed values for missing data. Kaplan-Meier survival curves and a Cox proportional hazards model were used to compare mortality at 6 months between the groups in the intention-to-treat population. The proportional hazards assumptions were evaluated with the log-cumulative hazard plot and martingale-based residuals; the assumptions were met. The observation was censored in the survival analysis if the patient was withdrawn from the study or was still alive at the end of the 6-month follow-up. Analyses were adjusted with the following prognostic factors: age, sex, time to return of spontaneous circulation, cooling rate, and site.³² In addition, the global fractional anisotropy and diffusivity values were used as factors associated with 6-month mortality after adjustment for age, sex, group, and site.

A 2-sided P value of less than .05 was considered statistically significant. Secondary end points were not adjusted for multiplicity and were therefore described as exploratory. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc).

Turku University Hospital recruited patients between August 2009 and September 2014; for Helsinki University Hospital, the corresponding dates were between October 2012 and September 2014; and the 6-month follow-up was completed during March 2015. A total of 224 patients were screened for eligibility and of these, 110 (aged 24 to 76 years) were enrolled with 55 randomly assigned to the xenon group and 55 to the control group (Figure 1). The patient characteristics of the 2 randomized groups were similar (Table 1). One patient in the xenon group was withdrawn from the study 6 days after the index event by the next of kin.

The mean end-tidal xenon concentration was 48.2% (SD, 3.8%) and the range was 41.4% to 56.9%. Neither core temperatures on admission to the intensive care unit nor during treatment and intervention differed between the groups; time from cardiac arrest to hypothermia target was also similar (Table 1 and eTable 4 in Supplement 2). There were no differences in the routinely measured laboratory parameters (eTable 4). Decisions to withdraw life-sustaining treatment were based on a consensus agreement that there was a poor neurological outcome (eTable 5). Of the 34 patients who died, 29 (85.3%) had a neurological mode of death (eTable 6).

Diffusion tensor MRI data for the tract-based spatial statistics analysis were obtained from 48 patients in the xenon group and 49 patients in the control group a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. At 6 months, 75 patients (68.2%) were alive and able to provide data for follow-up. The reasons for missing MRI data appear in Figure 1. Using tract-based spatial statistics analysis, a statistical parametric map containing 119 013 voxels was created to visualize the spatial distribution of areas with significantly lower fractional anisotropy in the control group (Figure 2). The fractional anisotropy was significantly lower in 41.7% of the voxels in the control group than in the xenon group (ie, 58.3% of the voxels did not differ between the groups). The tract-wise distribution of the percentages appears in Figure 2. None of the voxels revealed significantly lower fractional anisotropy values in the xenon group.

The mean global fractional anisotropy values of all voxels presented in Figure 2 were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group (P = .03; Table 2). The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1% to 6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005 to 0.027], P = .006). The mean radial diffusivity value was 0.598 (SD, 0.051) for the xenon group and 0.619 (SD, 0.062) for the control group. The adjusted radial diffusivity value was 3.9% lower (95% CI, 0.5%-7.4%) in the xenon group than in the control group (adjusted mean difference, −0.024 [95% CI, −0.046 to −0.003], P = .03; Table 2). Collectively, these quantitative differences in diffusion tensor MRI values indicated that there had been more severe disruption of white matter in the control group.

Of the diffusion tensor MRI measures, global fractional anisotropy exhibited the best independent predictive value for mortality during the 6-month follow-up period (mean [SD] of 0.433 [0.026] in the surviving patients vs 0.407 [0.035] in those who died per 0.01-unit increase in fractional anisotropy); the age-, sex-, group-, and site-adjusted hazard ratio was 0.81 (95% CI, 0.69-0.94; P = .006) (eTable 7 in Supplement 2). The mean global fractional anisotropy was 6.4% higher (95% CI, 3.3%-9.5%) in the surviving patients than in those who died.

In the intention-to-treat population, the Kaplan-Meier survival estimate after 6-month follow-up was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01], P = .053; eFigure 1 in Supplement 2).

At 6 months, neurological outcome was not significantly different between the groups as assessed with the CPC (median score of 1 [IQR, 1-5] for the xenon group and 1 [IQR, 1-5] for the control group; median difference, 0 [95% CI, 0-0], P = .93) or the mRS (median score of 1 [IQR, 0-6] for the xenon group and 1 [IQR, 0-6] for the control group; median difference, 0 [95% CI, 0-0], P = .68).

Similarly, the rates of serious adverse events were not significantly different between the groups at 6 months (Table 3 and eTable 8 in Supplement 2). In addition, there was not any difference in neurocognitive outcome measures of MMSE (median of 29 [IQR, 27-30] for the xenon group and median of 29 [IQR, 28-30] for the control group) and NIHSS (median of 0 [IQR, 0-0] for the xenon and control groups).

Quiz Ref IDThe principal finding was that inhaled xenon in combination with therapeutic hypothermia treatment preserved white matter tracts better than hypothermia treatment alone in survivors of cardiac arrest. This was reflected by higher fractional anisotropy values indicative of an attenuation of ongoing disruption of white matter microintegrity, and the lower radial diffusivity, a reflection of less demyelination of the white matter tracts.

Diffusion tensor MRI and tract-based spatial statistics represent an automated quantitative assessment of injury to white matter tracts.²⁵ The fractional anisotropy, acquired from diffusion tensor MRI, is a correlate of the microintegrity of white matter tracts.²¹ Lower fractional anisotropy values obtained within 3 weeks of cardiac arrest have been associated with a poor 1-year neurological outcome.³³ We analyzed the discriminating value of the global fractional anisotropy for survival to estimate whether a clinical benefit could accrue from the higher fractional anisotropy values in the xenon group. We found that the mean global fractional anisotropy value was significantly higher among survivors and in the xenon group compared with those who died and those in the control group. In addition, of all the diffusion tensor MRI measures, lower fractional anisotropy was associated with mortality during the 6-month follow-up.

With regard to the other diffusion tensor MRI parameters, each of the diffusivity values was lower in the xenon group; however, the reductions only achieved statistical significance for radial diffusivity (Table 2). In an earlier study in which patients with severe brain injury were scanned at times varying from 5 days to 7 weeks after cardiac arrest, the radial diffusivity values were significantly higher than the corresponding values from healthy volunteers.³⁴ The mean diffusivity data from 14 patients treated with hypothermia and who received an MRI scan within 3 days of their cardiac arrest did not predict outcome.³⁵ In this study, higher unadjusted radial and mean diffusivity values were independent predictors of mortality during the 6-month follow-up. However, none of the adjusted diffusivity values could clearly discriminate between survivors and nonsurvivors and hence the clinical value of these metrics remains unproven.

Although the statistically significant difference (P = .006) between patients treated with xenon and those untreated for adjusted mean global fractional anisotropy values was only 3.8% (adjusted mean difference of 0.016), this magnitude of change needs to be considered in the context of the statistically significant difference between survivors and those who died of 6.4% (eTable 7 in Supplement 2). In addition, a diluting effect of voxels, without significant difference between the groups (displayed in green in Figure 2) in the final tract-based spatial statistical analysis, resulted in reduced absolute mean difference in the global fractional anisotropy values (Table 2). Thus, the treatment effect size of xenon on global fractional anisotropy was more than 50% of the difference in this primary outcome measure observed between survivors and those who died. Furthermore, the severity of observed widespread injury was demonstrated by the finding that 41.7% of the white matter tracts on average, including major commissural, associative, and projection fibers, were significantly more severely injured in the control group than in the xenon group. These fibers are involved in multiple important cognitive functions, such as attention, memory, language, emotions, auditory, visual and executive processing, and motor functions of the body.

The volume of white matter constitutes 50% of total brain volume in humans and is highly vulnerable to even brief ischemia.³⁶ The present results indicate that the higher radial diffusivity (demyelination) was mainly responsible for the lower fractional anisotropy in patients in the control group.²⁴ An earlier study revealed that N-methyl-D-aspartate receptors are expressed in myelin of white matter oligodendrocytes and become activated during ischemia³⁷; xenon is a N-methyl-D-aspartate receptor antagonist and a competitive inhibitor at the glycine coactivation site of that receptor.^7,8 Although not demonstrated here, it is possible that sensitive tests of neurocognitive function in an appropriately powered clinical trial may translate the improvement in white matter into clinical benefits. This hypothesis warrants further investigation.

Quiz Ref IDAlthough a benefit of xenon on white matter damage was observed, there were no significant differences in the exploratory analysis in either neurological (CPC or mRS score; Table 3) or cognitive outcomes (NHISS or MMSE score) between the 2 treatment groups. The study was underpowered to detect a statistically significant difference in clinical outcome due to the rarity of severe neurological impairment in long-term survivors after cardiac arrest; about 90% of patients who experience cardiac arrest and are alive at the 6-month follow-up have experienced a good neurological outcome (CPC score of 1 or 2).^38-41 In both groups, the MMSE score was 29 of a maximum score of 30; this was very similar to the score of 28 that was reported in a large targeted temperature management study comparing comatose cardiac arrest survivors treated at 33°C and 36°C, and may reflect the small effect size that this test is capable of eliciting.⁴⁰ Therefore, in subsequent studies, more sensitive methods will be needed for assessing functional neurocognitive disorders.

The study had several limitations. First, the secondary end points were not adjusted for multiplicity and therefore were described as exploratory. Second, in the analysis of secondary end points, we did not have sensitive enough neurocognitive tests to measure subtle degrees of functional disability in the small number of patients that could be assessed. Third, our primary end point was based on a single time point in the early stage of evolving brain injury; it remains to be determined whether the improvement in the diffusion tensor MRI metrics persists and can contribute to a long-term clinical benefit. Fourth, all patients received delayed xenon intervention and therefore it is possible that the observed effect on white matter may have been different if the xenon intervention had been initiated earlier after the ischemic event. Fifth, although more than 80% of the deaths in this study were due to severe ischemic brain injury, underlying cardiac disease also may have contributed to poor outcomes, therefore, it is unknown whether some patients might have benefitted from the improved cardiovascular stability associated with xenon.¹³ Sixth, the sample size calculation of the present study was based on an unrealistic assumption of the absolute difference of fractional anisotropy values between the groups. Nonetheless, because the variance of the variable was proportionally smaller, there was a statistically significant difference between the groups; however, the absolute difference in fractional anisotropy was small. Seventh, the predictive value of global fractional anisotropy for survival needs to be prospectively validated before designating the improvement in white matter injury seen in the xenon group as a marker for improved survival.

Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest.

Corresponding Author: Timo Laitio, MD, PhD, Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, POB 52, Turku FI-20521, Finland (timo.laitio@elisanet.fi).

Author Contributions: Dr T. Laitio had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: R. Laitio, Parkkola, Saunavaara, Roine, Saraste, Scheinin, Maze, T. Laitio.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: R. Laitio, Arola, Virtanen, Parkkola, Saunavaara, Tiainen, Saraste, Airaksinen, Maze, Vahlberg, T. Laitio.

Critical revision of the manuscript for important intellectual content: R. Laitio, Hynninen, Arola, Parkkola, Saunavaara, Bäcklund, Roine, Grönlund, Ylikoski, Wennervirta, Silvasti, Nukarinen, Tiainen, Saraste, Pietila, Airaksinen, Valanne, Martola, Silvennoinen, Scheinin, Harjola, Niiranen, Korpi, Varpula, Inkinen, Olkkola, Maze, Vahlberg, T. Laitio.

Statistical analysis: Virtanen, Saunavaara, Vahlberg, T. Laitio.

Obtained funding: Roine, T. Laitio.

Administrative, technical, or material support: R. Laitio, Hynninen, Virtanen, Parkkola, Saunavaara, Roine, Grönlund, Ylikoski, Wennervirta, Bäcklund, Silvasti, Nukarinen, Saraste, Airaksinen, Martola, Silvennoinen, Scheinin, Niiranen, Korpi, Varpula, Olkkola, Maze, T. Laitio.

Study supervision: R. Laitio, Hynninen, Parkkola, Saunavaara, Roine, Saraste, Airaksinen, Scheinin, T. Laitio.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr R. Laitio reported receiving travel reimbursement from Octapharma. Dr Saraste reported serving as a consultant to GE and Novartis; receiving funding from Abbott and Actelion for educational lectures; and receiving travel reimbursement from Novartis, Lilly, and Abbott. Dr Airaksinen reported receiving funding from AstraZeneca, Boehringer Ingelheim, Cardiome, and Pfizer for educational lectures. Dr Inkinen reported receiving travel reimbursement from Orion. Dr Maze reported being a founder, board director, and equity shareholder of Neuroprotexeon Company, which intends to commercialize the use of xenon for ongoing acute neurological injury, including its use in successfully resuscitated patients after out-of-hospital cardiac arrest. Dr T. Laitio reported receiving institutional funding from Neuroprotexeon Company. No other disclosures were reported.

Funding/Support: The study was funded by the Academy of Finland and via clinical research funding from the Hospital District of Southwest Finland.

Role of the Funder/Sponsor: The Academy of Finland and the Hospital District of Southwest Finland 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.

Additional Contributions: We thank research nurses Keijo Leivo, RN (Turku University Hospital; who was compensated for his contribution), and Tuukka Tikka, RN (Helsinki University Hospital; who was compensated for his contribution), for taking care of the logistics in this study. We thank Michael E. Moseley, PhD (Stanford University, Stanford, California; who received no compensation), for his invaluable advice and comments during preparation of the manuscript.