Author + information
- Received June 9, 2017
- Revision received September 18, 2017
- Accepted September 18, 2017
- Published online November 20, 2017.
- Olli Arola, MDa,
- Antti Saraste, MD, PhDb,
- Ruut Laitio, MD, PhDa,
- Juhani Airaksinen, MD, PhDb,
- Marja Hynninen, MD, PhDc,
- Minna Bäcklund, MD, PhDc,
- Emmi Ylikoski, MD, PhDc,
- Johanna Wennervirta, MD, PhDc,
- Mikko Pietilä, MD, PhDb,
- Risto O. Roine, MD, PhDd,
- Veli-Pekka Harjola, MD, PhDe,
- Jussi Niiranen, MDf,
- Kirsi Korpi, MDf,
- Marjut Varpula, MD, PhDf,
- Harry Scheinin, MD, PhDa,
- Mervyn Maze, MB, ChBg,
- Tero Vahlberg, MSch,
- Timo Laitio, MD, PhDa,∗ (, )
- for the Xe-HYPOTHECA Study Group
- aDivision of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, University of Turku, Turku, Finland
- bHeart Center, Turku University Hospital and University of Turku, Turku, Finland
- cDivision of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- dDivision of Clinical Neurosciences, University of Turku, Turku University Hospital, Turku, Finland
- eEmergency Medicine, Department of Emergency Medicine and Services, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- fDepartment of Cardiology, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- gDepartment of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California
- hDepartment of Biostatistics, University of Turku and Turku University Hospital, Turku, Finland
- ↵∗Address for correspondence:
Dr. Timo Laitio, Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, POB 52, FI-20521, Turku, Finland.
Background The authors previously reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA).
Objectives A pre-defined secondary objective was to assess the effect of inhaled xenon on myocardial ischemic damage in the same study population.
Methods A total of 110 comatose patients who had experienced OHCA from a cardiac cause were randomized to receive either inhaled xenon (40% end-tidal concentration) combined with hypothermia (33°C) for 24 h (n = 55; xenon group) or hypothermia treatment alone (n = 55; control group). Troponin-T levels were measured at hospital admission, and at 24 h, 48 h, and 72 h post-cardiac arrest. All available cases were analyzed for troponin-T release.
Results Troponin-T measurements were available from 54 xenon patients and 54 control patients. The baseline characteristics did not differ significantly between the groups. After adjustments for age, sex, study site, primary coronary percutaneous intervention (PCI), and norepinephrine dose, the mean ± SD post-arrival incremental change of the ln-transformed troponin-T at 72 h was 0.79 ± 1.54 in the xenon group and 1.56 ± 1.38 in the control group (adjusted mean difference −0.66; 95% confidence interval: −1.16 to −0.16; p = 0.01). The effect of xenon on the change in the troponin-T values did not differ in patients with or without PCI or in those with a diagnosis of ST-segment elevation myocardial infarction (group by PCI or ST-segment elevation myocardial infarction interaction effect; p = 0.86 and p = 0.71, respectively).
Conclusions Among comatose survivors of OHCA, in comparison with hypothermia alone, inhaled xenon combined with hypothermia suggested a less severe myocardial injury as demonstrated by the significantly reduced release of troponin-T.
Throughout Europe, the in-hospital mortality of successfully resuscitated out-of-hospital cardiac arrest (OHCA) patients ranges from 41% to 86% (1–3). International guidelines for post-resuscitation care recommend targeted temperature management with target temperatures between 32°C and 36°C (4,5).
Post-cardiac arrest syndrome is a complex combination of ischemic cerebral and myocardial injury combined with a reperfusion response leading to different combinations of multiorgan failure; it is responsible for significant morbidity and mortality as a consequence of whole-body ischemia (4). Although ischemic brain injury is the leading cause for in-hospital deaths after OHCA, myocardial dysfunction and circulatory failure account for most deaths during the first 3 days (6,7). In addition, the severity of myocardial injury affects both short- and long-term mortality (8–10). Therefore, new strategies to attenuate the ischemic reperfusion myocardial injury leading to cardiomyocyte death after cardiac arrest are needed.
Earlier clinical studies in patients with and without cardiovascular disease have demonstrated that inhalation of the noble gas xenon may be cardioprotective by decreasing heart rate without affecting either cardiac conductance or contractility (11–13). In animal models, xenon has provided cardioprotection by pre- and post-conditioning mechanisms (14,15). We have reported previously that xenon combined with hypothermia confers neuroprotection by attenuating the brain white matter injury more than hypothermia alone in comatose survivors of cardiac arrest (16). Inhaled xenon is feasible, well-tolerated, and safe in OHCA patients (17). The purpose of this study was to evaluate the effect of xenon on myocardial damage in comatose survivors of OHCA.
The Xe-HYPOTHECA trial (Effect of Xenon and Therapeutic Hypothermia, on the Brain and on Neurological Outcome Following Brain Ischemia in Cardiac Arrest Patients; NCT00879892) was a randomized 2-group, single-blinded phase II clinical drug trial at 2 multipurpose intensive care units (ICU) in Finland. The ethics committee of the Hospital District of Southwest Finland and the institutional review boards of the Helsinki University Hospital and the Finnish Medicine Agency approved the study. As described previously, 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 Helsinki. Written informed assent was obtained from the next-of-kin or from the legal representative of the patient within 4 h after hospital admission. The patient’s family was informed about the right to withdraw from the study at any point, but the data collected until possible withdrawal could be used in the analyses as predefined in the protocol. Patients were informed accordingly if they regained consciousness (16,17).
The patients were allocated in a 1:1 ratio with random block sizes of 4, 6, and 8 to receive either therapeutic hypothermia treatment alone for 24 h (designated as the control group) or inhaled xenon (LENOXe, Air Liquide Medical, Düsseldorf, Germany) in combination with hypothermia for 24 h (designated as the xenon group). The clinical investigators enrolled the patients, and after assent was received, randomization was performed with sealed computer-randomized envelopes followed by the assigned intervention. Due to practical and safety considerations, the personnel involved in the patient treatment could not be blinded. A mode of death was classified as neurological, cardiac, or multiorgan as described previously (16). A local neurological prognostication consensus was used in decisions to withdraw life-sustaining treatment (16).
In the Xe-HYPOTHECA trial, the primary hypothesis was that xenon would attenuate white matter injury after OHCA. We have previously published the feasibility and cardiac safety of inhaled xenon after OHCA, and the effect of inhaled xenon on cerebral white matter damage and on the clinical outcome at 6 months in comatose survivors of OHCA (16,17). The latter report also included the protocol of the Xe-HYPOTHECA trial. The effect of xenon on myocardial injury was a pre-defined secondary endpoint.
Consecutive comatose survivors of OHCA admitted to Turku and Helsinki University hospitals were screened for eligibility. The main criteria for inclusion were witnessed OHCA from shockable initial rhythm, that is, ventricular fibrillation or pulseless ventricular tachycardia, and restoration of spontaneous circulation within 45 min. Details of inclusion and exclusion criteria are presented in Online Table 1.
If indicated, coronary angiography interventions were performed before ICU admission. There was adherence to a detailed treatment protocol that included hemodynamic and ventilator targets during cooling and normothermia as described previously (17). The sedation depth was assessed with the Richmond Agitation Sedation Scale every 4 h from admission into intensive care to the end of hypothermia treatment. The patients were cooled with an invasive intravascular temperature management device, the Alsius CoolGard 3000 thermal regulation system (Zoll Medical Corporation, Chelmsford, Massachusetts) to target a core temperature of 33°C, which was maintained for 24 h. Inhaled xenon was initiated immediately after randomization through a closed-circuit ventilator (PhysioFlex, Dräger, Lübeck, Germany). The end-tidal xenon concentration was adjusted to at least 40% and delivered until start of rewarming. The pre-defined arterial partial oxygen pressure was maintained during hypothermia treatment and the ventilator was adjusted if indicated as described previously (17).
Troponin-T was assessed at admission (baseline), and at 24, 48, and 72 h after OHCA. Until March 1, 2012, troponin-T was analyzed with a limit of detection of 0.03 μg/l (Electrochemiluminescence immunoassay, ECLIA Troponin-T Cardiac, Roche Diagnostics, Mannheim, Germany). Thereafter, a high-sensitivity cardiac troponin-T assay was used with a limit of detection of 5 ng/l (Electrochemiluminescence immunoassay, ECLIA Troponin T high-sensitive, Roche Diagnostics). The high-sensitivity troponin-T values were transformed to the corresponding μg/l values. The diagnosis of acute myocardial infarction was based upon the latest recommendations (8), namely, the ST-segment elevation (STEMI) and non–ST-segment elevation myocardial infarctions (NSTEMI) were defined by increased blood levels of cardiac troponin-T above the baseline value together with clinical features, including electrocardiographic findings in the field, and on hospital arrival and at 24, 48, and 72 h after cardiac arrest; angiographic findings; and possible autopsy report. The angiographic and electrocardiographic findings were analyzed by experienced cardiologists who were blinded to the intervention group. Acute kidney injury was diagnosed as previously described (16,17).
The sample size of 110 patients was based on a power analysis of the fractional anisotropy values from brain magnetic resonance imaging, that is, the primary endpoint of the Xe-HYPOTHECA trial (16). The Shapiro-Wilk W test was used to evaluate the normality of all continuous variables. Two-sample Student's t-test and Mann-Whitney U test were used to compare continuous characteristic variables between groups. Categorical characteristic variables were analyzed with the chi-square test or Fisher exact test. The correlations between the increment in the level of troponin-T from hospital admission to 72 h and the dose of administered drugs (i.e., norepinephrine, epinephrine, dobutamine, dopamine, levosimendane, furosemide, propofol, midazolam, fentanyl, and insulin), and hemodynamic parameters (mean and systolic arterial pressure, central venous pressure, heart rate in 2-min [Turku] or 5-min [Helsinki] epochs) during the first 24 h and at 72 h after ICU admission were calculated using Spearman correlation coefficients. The differences in changes in troponin-T values between groups were analyzed using repeated measures analysis of covariance adjusted for age, sex, study site, percutaneous coronary intervention (PCI), and cumulative norepinephrine use in the first 24 h after ICU admission. A natural logarithmic (ln) transformation was performed for troponin-T values before analyses due to their positively skewed distribution. Results of troponin-T values at each time point were presented as geometric mean (95% confidence interval [CI]). The geometric means were calculated by back-transforming the means of ln-transformed troponin-T values to the original scale. An unstructured covariance matrix was used in the repeated measures model. An all-available case analysis was applied to the troponin-T. The effect of troponin-T on survival was analyzed with Cox regression adjusted for age, sex, study site, and group. Results are expressed using hazard ratios (HRs) with 95% CIs. A 2-sided p value <0.05 was considered statistically significant. Statistical analyses were performed using SAS System for Windows, version 9.4 (SAS Institute, Cary, North Carolina).
Turku University Hospital recruited patients between August 2009 and September 2014, and Helsinki University Hospital, between October 2012 and September 2014, respectively. The 6-month follow-up was completed by March 2015. Altogether, 224 patients were screened for eligibility, 110 were enrolled, with 55 being randomly assigned to the xenon group and 55 to the control group. At 6 months after OHCA, 15 of the 55 xenon patients and 19 of the 55 control patients had died. Details of the deaths, mode of deaths, and withdrawals are presented in Online Table 2.
The baseline characteristics of the 54 xenon and 54 control patients for whom we had troponin-T data did not differ between the groups (Table 1). The reasons for missing troponin-T data are summarized in Online Table 3. The number of PCIs, diseased coronary vessels, and patients with incident coronary artery disease on hospital arrival were similar in the 2 groups (Table 2). A precise status of the coronary arteries could not be determined in 7 xenon patients and in 4 of the control patients because neither coronary angiography nor autopsy was performed on these patients. Of the patients with STEMI (n = 36), 14 of the 17 in the xenon group and 16 of the 19 in the control group were treated with PCI on hospital arrival. In patients with NSTEMI (n = 64), 2 in the control group and 1 in the xenon group were treated with PCI on hospital arrival. Eight patients without an acute myocardial infarction did not have occlusive coronary disease; etiological reasons for cardiac arrest were arrhythmogenic heart disease in 5 xenon patients and in 1 control patient, thyrotoxicosis in 1 control patient, and dilated cardiomyopathy in 1 control patient. As summarized in Online Table 4, baseline and peak values of plasma creatinine and the incidence of acute kidney injury did not differ between the groups.
The absolute values of troponin-T at hospital arrival, and at 24, 48, and 72 h in both groups are presented in the Central Illustration. The baseline values at hospital arrival did not differ between the xenon and control groups (geometric mean [95% CI] 0.100 μg/l [0.070 to 0.141 μg/l] vs. 0.098 μg/l [0.071 to 0.135 μg/l], respectively). At 72 h after OHCA, the geometric mean troponin-T was 111% higher in the control group than in the xenon group (geometric mean [95% CI] 0.464 μg/l [0.300 to 0.716 μg/l] vs. 0.220 μg/l [0.128 to 0.380 μg/l], respectively) as illustrated in the Central Illustration and in Online Table 5.
Adjusted geometric means of troponin-T peaked at 24 h in both groups with a significant increase from the baseline values (p < 0.0001). A decline of troponin-T from the peak to 72 h differed significantly between the groups (p = 0.0008) with a significant decline of 44.8% (p < 0.0001) in the xenon group and a nonsignificant decline of 11.3% (p = 0.56) in the control group (Central Illustration, Online Table 5). In NSTEMI patients, the decline from peak to 72 h was significantly different between the groups (p = 0.0004): a significant decline of 48.6% within the xenon group (p < 0.0001), but a nonsignificant increase of 0.9% within the control group (p = 0.93). In STEMI patients, the difference of troponin-T decline between the groups was nonsignificant (p = 0.61); the decline from peak to 72 h was significant within the xenon group (p = 0.01), but nonsignificant within the control group (p = 0.053) (Online Table 6). Geometric mean (95% CI) of troponin-T was significantly higher in STEMI than in NSTEMI at each time point after baseline (Online Table 7).
The change over time of the levels of troponin-T differed between the xenon and the control groups (time by group interaction p = 0.003); after adjustment for age, sex, study site, PCI, and norepinephrine, the increase of troponin-T values from hospital admission to 72 h was significantly less in the xenon group than in the control group (adjusted mean difference of ln-transformed values: −0.66; 95% CI: −1.16 to −0.16; ratio of adjusted geometric means: 0.52; 95% CI: 0.31 to 0.85; p = 0.01) (Table 3).
The effect of xenon on the change in the troponin-T values did not differ in patients with or without PCI or in those with a diagnosis of STEMI (PCI or STEMI by group by time interaction effect; p = 0.72 and p = 0.29, respectively).
Predictive value of troponin-T for mortality at 6 months
The adjusted absolute value of each time point after baseline and the incremental change from baseline to each of time point of troponin-T release had a significant predictive value for mortality at 6 months after the index event within the groups and in the whole population (Online Table 8). The association of troponin-T release on survival did not differ between the groups (for all time points in the group by troponin-T interaction p > 0.10).
Intravenous drugs and sedation depth
Significantly less propofol was administered in the xenon group compared with the control group during the first 72 h (Table 4), but the propofol dose of the second and the third day after hospital arrival did not differ between the groups (p = 0.20 and p = 0.13, respectively). None of the other intravenous medications administered during the first 72 h differed significantly between the groups (Table 4, Online Table 9). The mean sedation depth according to the Richmond Agitation Sedation Scale until the end of hypothermia treatment was 4.3 ± 0.6 in the control group and 4.4 ± 0.6 in the xenon group (p = 0.17).
The median (interquartile range) heart rate was significantly lower in the xenon group than in the control group during the first 72 h. The other pre-defined hemodynamic parameters did not differ between the groups during the first 24 or 72 h (Table 4).
Correlations between troponin-T, intravenous drugs, and hemodynamic parameters
In the xenon group, the incremental change in the troponin-T values from hospital admission to 72 h displayed a significant correlation with norepinephrine (r = 0.51; p = 0.0001) and dobutamine (r = 0.27; p = 0.049) doses during the first 72 h after ICU admission. There were no other significant correlations between the incremental change of troponin-T from hospital admission up to 72 h and the administered drugs or hemodynamic parameters, or between propofol and any of the vasoactive drugs (as listed in Table 4 and Online Table 9) in the 2 groups or within the whole population (correlation data not shown).
The main finding of this study was that among comatose survivors of OHCA, inhaled xenon combined with mild therapeutic hypothermia resulted in a reduced myocardial injury when compared with that achieved by hypothermia alone as demonstrated by the significantly lower release of troponin-T from baseline to 72 h after OHCA in the xenon group. The incremental change of troponin-T was also associated with higher mortality at 6 months.
Current results revealed significantly lower troponin-T release in the xenon group than in the control group at 72 h, but not at 24 and 48 h, explaining why the area under the curve remained nonsignificant. However, release profiles of troponin-T from baseline to 72 h differed significantly between the groups, with a significant decline of 44.8% in the xenon group and a nonsignificant decline of 11.3% in the control group from the peak at 24 h to 72 h. The decline was even more pronounced between the groups in patients with NSTEMI, with a significant decline in the xenon group as compared with a nonsignificant increase in the control group from the peak to 72 h. Although the decline was significant only in the xenon group, the release profile of the control group was very similar to a recently published population of 699 OHCA patients, with a decline of 10.8% (10). Furthermore, current patients with STEMI had a significantly higher troponin-T release than those with NSTEMI, which is in line with earlier studies revealing a similar difference in troponin-T and higher infarct mass in STEMI patients (18). According to earlier firm evidence, all single-point measures of troponin-T at 24, 48, and 72 h (and also at 96 h) correlate significantly well with the final extent of infarct mass (18). Consequently, our interpretation of the current result is that the single-point values of troponin-T, rather than the area under the curve, were likely to be reliable estimates of the ongoing process of ischemia/reperfusion injury, and the difference between the groups reflects a significant treatment effect of xenon observed over the span of 72 h.
The positive effect of xenon was independent of age, sex, study site, dose of norepinephrine, and performed PCI. The effect of xenon on the troponin-T release was similar in patients with or without PCI or with a diagnosis of STEMI, as well as in either survivors or nonsurvivors. Furthermore, the severity of coronary artery disease, as evaluated by patient history, coronary angiography, and autopsy report (when available), was comparable in the study groups, suggesting that the effect of xenon was not likely to be modified by the different causes of myocardial injury after OHCA. As discussed later in more detail, none of the other major confounding variables included in the model either differed between the groups or exhibited any correlation with the release of troponin-T. Therefore, xenon was a significant independent factor attenuating the severity of the myocardial injury after OHCA.
Several animal experiments with models of ischemic myocardial injury with and without hypothermia have demonstrated that xenon’s pre- and post-conditioning effects lead to a reduction in the myocardial infarct size (14,15,19–22). In this study, the effect on the troponin-T release was likely due to a post-conditioning effect, because xenon inhalation was initiated with a mean delay of 4 h after OHCA. Multiple molecular targets have been identified as being implicated in xenon’s cardioprotective conditioning effect. These include prosurvival signaling kinases, such as protein kinase cƐ (PKCƐ), protein kinase B (Akt), and glycogen synthase kinase 3 β (GSK-3 β), p38 mitogen-activated protein kinase (MAPK), MAPK-activated kinase-2, heat-shock protein 27, and extracellular signal-regulated kinases 1/2 (23–26). Moreover, phosphorylation of PKCƐ, Akt, and GSK-3 β by xenon has been reported to inhibit Ca2+-induced mitochondrial permeability transition pore opening, which is known to preserve mitochondrial function and prevent ischemic reperfusion injury and cell death (27).
We also analyzed the predictive value of troponin-T for all-cause mortality at 6 months after OHCA to estimate further whether a clinical benefit would accrue from the significantly lower troponin-T values in the xenon group. We found that all the time points of troponin-T after the baseline value within the groups and in the whole population had a predictive value for all-cause mortality at 6 months after OHCA. This finding is in agreement with the latest consensus statement of the Joint Task Force and recent trials declaring that troponin-T release has an independent predictive value for both short- and long-term morbidity and mortality in cardiac arrest patients, as well as in all intensive care patients, regardless of the underlying disease (8–10).
In earlier clinical trials with cardiovascular surgical patients, xenon anesthesia has been characterized as conferring cardiovascular stability by maintaining systolic blood pressure, myocardial contractility, and stroke volume, as well as preload, accompanied by an inotrope-sparing effect (11–13,28–30). In the current trial with long-term xenon inhalation, the doses of vasoactive medication did not differ significantly between the groups. Most importantly, doses of both norepinephrine and dobutamine showed a significant positive correlation with troponin-T release in the xenon group only. Consequently, vasoactive medication was unlikely to have been responsible for the more severe myocardial injury in the control group.
The xenon group required significantly less propofol to achieve the predefined deep level of sedation, as determined by a Richmond Agitation Sedation Score of at least 4. However, the difference was not sustained during the following days after discontinuation of xenon inhalation. Animal and clinical studies have demonstrated that propofol mitigates oxidative stress and potentially protects the heart against a post-ischemic reperfusion injury by decreasing troponin-T release after coronary artery bypass surgery (31–35). Despite the possible cardioprotective properties of propofol, there was no correlation between the administered dose and the troponin-T release within the groups in this study. Therefore, it is unlikely that the administration of propofol use had any significant impact on the current results.
Xenon’s heart rate–decreasing properties have been well documented (11,13,17,28,29). In our study, the combination of xenon and hypothermia resulted in a significantly lower heart rate when compared with hypothermia alone, with this effect lasting at least up to 72 h after OHCA. Interestingly, a recent trial demonstrated that pronounced sinus bradycardia during hypothermia was associated with improved outcome, and it was proposed to represent an independent marker of favorable neurocognitive outcome (36). Therefore, one could argue that xenon’s ability to reduce the heart rate may have some beneficial clinical value in cardiac arrest patients. However, this was not supported by the current results because no correlation could be detected between heart rate and troponin-T release.
First, neither coronary angiography nor autopsy was performed in 7 xenon and in 4 control patients, and therefore, the severity of coronary disease could not be evaluated in these patients; the diagnosis of acute myocardial infarction was based on clinical data, troponin-T release, and serial electrocardiograms. Second, it was not possible to reliably distinguish between a cardiac and a noncardiac cause of death because all patients with severe ischemic cerebral injury had also myocardial damage due to a global, as well as an occlusive, ischemia (16). Of the nonsurvivors, 85% did not regain consciousness due to a severe ischemic encephalopathy, and the deaths were eventually classified as neurological mode of death (16). Only 2 deaths from both groups were classified into a category of cardiovascular mode of death. Therefore, this study was not sufficiently powered to address xenon’s long-term effect on either cardiac or all-cause mortality. A large phase III trial is needed to establish whether these observations actually translate into a clinical benefit.
Among comatose survivors of OHCA, inhaled xenon combined with mild therapeutic hypothermia results in less severe myocardial injury than hypothermia alone as determined by the lower release of troponin-T from baseline to 72 h after OHCA in the xenon group. Although these observations do not provide a mechanistic explanation for the present findings, we speculate that xenon may provide a protective post-conditioning effect against ongoing myocardial injury. These findings will need further evaluation in an adequately powered trial to address the clinical effect of xenon inhalation on long-term outcome among survivors of OHCA.
COMPETENCY IN MEDICAL KNOWLEDGE: Inhaled xenon combined with mild therapeutic hypothermia attenuates myocardial injury among survivors of OHCA.
TRANSLATIONAL OUTLOOK: Randomized trials of larger scope will be needed to determine whether the reduction in troponin-T release achieved with combined xenon and hypothermia translates into long-term clinical benefit compared with hypothermia alone.
The Xe-HYPOTHECA Study Group includes: Sami Virtanen, MD, Riitta Parkkola, MD, PhD (Department of Radiology, University of Turku, Turku University Hospital, Turku, Finland), Jani Saunavaara, PhD (Department of Medical Physics, Turku University Hospital and University of Turku, Turku, Finland), Juha Martola, MD, PhD, Heli Silvennoinen, MD, PhD (Department of Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland), Marjaana Tiainen, MD, PhD (Department of Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland), Juha Grönlund, MD, PhD, Outi Inkinen, MD (Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, University of Turku, Turku, Finland), and Päivi Silvasti, MD, Eija Nukarinen, MD, and Klaus T. Olkkola, MD, PhD (Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland).
The authors thank research nurses Keijo Leivo and Tuukka Tikka (Helsinki University Hospital), both of whom were compensated for their contribution, for taking care of the logistics of this study.
The study was funded by the Academy of Finland and by clinical research funding from the Hospital District of Southwest Finland. The study was academic, that is, the funding organizations did not have any role in design and conduct of the study, collection, management, analysis, and interpretation of the data and preparation, review, or approval of the manuscript. Dr. R. Laitio is a paid governmental consultant official for the National Supervisory Authority for Welfare and Health. Dr. Maze is a founder, board director, and equity shareholder of NeuroproteXeon, a company that intends to commercialize the use of xenon for ongoing acute neurological injury, including its administration to successfully resuscitated patients after out-of-hospital cardiac arrest. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- hazard ratio
- intensive care unit
- non–ST-segment elevation myocardial infarction
- out-of-hospital cardiac arrest
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received June 9, 2017.
- Revision received September 18, 2017.
- Accepted September 18, 2017.
- 2017 American College of Cardiology Foundation
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