The predictive value of highly malignant EEG patterns after cardiac arrest: evaluation of the ERC-ESICM recommendations.

PURPOSE: The 2021 guidelines endorsed by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) recommend using highly malignant electroencephalogram (EEG) patterns (HMEP; suppression or burst-suppression) at > 24 h after cardiac arrest (CA) in combination with at least one other concordant predictor to prognosticate poor neurological outcome. We evaluated the prognostic accuracy of HMEP in a large multicentre cohort and investigated the added value of absent EEG reactivity. METHODS: This is a pre-planned prognostic substudy of the Targeted Temperature Management trial 2. The presence of HMEP and background reactivity to external stimuli on EEG recorded > 24 h after CA was prospectively reported. Poor outcome was measured at 6 months and defined as a modified Rankin Scale score of 4-6. Prognostication was multimodal, and withdrawal of life-sustaining therapy (WLST) was not allowed before 96 h after CA. RESULTS: 845 patients at 59 sites were included. Of these, 579 (69%) had poor outcome, including 304 (36%) with WLST due to poor neurological prognosis. EEG was recorded at a median of 71 h (interquartile range [IQR] 52-93) after CA. HMEP at > 24 h from CA had 50% [95% confidence interval [CI] 46-54] sensitivity and 93% [90-96] specificity to predict poor outcome. Specificity was similar (93%) in 541 patients without WLST. When HMEP were unreactive, specificity improved to 97% [94-99] (p = 0.008). CONCLUSION: The specificity of the ERC-ESICM-recommended EEG patterns for predicting poor outcome after CA exceeds 90% but is lower than in previous studies, suggesting that large-scale implementation may reduce their accuracy. Combining HMEP with an unreactive EEG background significantly improved specificity. As in other prognostication studies, a self-fulfilling prophecy bias may have contributed to observed results.

Agreement between self-reported and objectively assessed physical activity among out-of-hospital cardiac arrest survivors.

BACKGROUND: Low level of physical activity is a risk factor for new cardiac events in out-of-hospital cardiac arrest (OHCA) survivors. Physical activity can be assessed by self-reporting or objectively by accelerometery. AIM: To investigate the agreement between self-reported and objectively assessed physical activity among OHCA survivors HYPOTHESIS: Self-reported levels of physical activity will show moderate agreement with objectively assessed levels of physical activity. METHOD: Cross-sectional study including OHCA survivors in Sweden, Denmark, and the United Kingdom. Two questions about moderate and vigorous intensity physical activity during the last week were used as self-reports. Moderate and vigorous intensity physical activity were objectively assessed with accelerometers (ActiGraph GT3X-BT) worn upon the right hip for 7 consecutive days. RESULTS: Forty-nine of 106 OHCA survivors answered the two questions for self-reporting and had 7 valid days of accelerometer assessment. More physically active days were registered by self-report compared with accelerometery for both moderate intensity (median 5 [3:7] vs. 3 [0:5] days; p < 0.001) and vigorous intensity (1 [0:3] vs. 0 [0:0] days; p < 0.001). Correlations between self-reported and accelerometer assessed physical activity were sufficient (moderate intensity: rs = 0.336, p = 0.018; vigorous intensity: rs = 0.375, p = 0.008), and agreements were fair and none to slight (moderate intensity: k = 0.269, p = 0.001; vigorous intensity: k = 0.148, p = 0.015). The categorization of self-reported versus objectively assessed physical activity showed that 26% versus 65% had a low level of physical activity. CONCLUSION: OHCA survivors reported more physically active days compared with the results of the accelerometer assessment and correlated sufficiently and agreed fairly and none to slightly.

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm: A Meta-Analysis.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Neurofilament light chain on intensive care admission is an independent predictor of mortality in COVID-19: a prospective multicenter study.

BACKGROUND: Neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total-tau protein (tau) are novel blood biomarkers of neurological injury, and may be used to predict outcomes in critical COVID-19. METHODS: A prospective multicentre cohort study of 117 consecutive and critically ill COVID-19 patients in six intensive care units (ICUs) in southern Sweden between May and November 2020. Serial NfL, GFAP and tau were analysed in relation to mortality, the Glasgow Outcome Scale Extended (GOSE) and the physical (PCS) and mental (MCS) components of health-related quality of life at one year. RESULTS: NfL, GFAP and tau on ICU admission predicted one-year mortality with an area under the curve (AUC) of 0.82 (95% confidence interval [CI] 0.74[Formula: see text]0.90), 0.72 (95% CI 0.62[Formula: see text]0.82) and 0.66 (95% CI 0.54[Formula: see text]0.77). NfL on admission was an independent predictor of one-year mortality (p = 0.039). Low NfL and GFAP values were associated with good PCS ([Formula: see text]45) at one year but not with good MCS ([Formula: see text]45) or GOSE ([Formula: see text]5). CONCLUSIONS: NfL on ICU admission was an independent predictor of mortality. High levels of NfL, GFAP and tau were associated with mortality but not with poor GOSE in survivors at one year. Low levels of NfL and GFAP were associated with improved physical health-related quality of life.

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial.

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). Main outcomes and measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Neuropsychological outcome after cardiac arrest: results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial.

BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA. METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes. RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance. CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.

Serum proteome profiles in patients treated with targeted temperature management after out-of-hospital cardiac arrest.

BACKGROUND: Definition of temporal serum proteome profiles after out-of-hospital cardiac arrest may identify biological processes associated with severe hypoxia-ischaemia and reperfusion. It may further explore intervention effects for new mechanistic insights, identify candidate prognostic protein biomarkers and potential therapeutic targets. This pilot study aimed to investigate serum proteome profiles from unconscious patients admitted to hospital after out-of-hospital cardiac arrest according to temperature treatment and neurological outcome. METHODS: Serum samples at 24, 48, and 72 h after cardiac arrest at three centres included in the Target Temperature Management after out-of-hospital cardiac arrest trial underwent data-independent acquisition mass spectrometry analysis (DIA-MS) to find changes in serum protein concentrations associated with neurological outcome at 6-month follow-up and targeted temperature management (TTM) at 33 °C as compared to 36 °C. Neurological outcome was defined according to Cerebral Performance Category (CPC) scale as "good" (CPC 1-2, good cerebral performance or moderate disability) or "poor" (CPC 3-5, severe disability, unresponsive wakefulness syndrome, or death). RESULTS: Of 78 included patients [mean age 66 ± 12 years, 62 (80.0%) male], 37 (47.4%) were randomised to TTM at 36 °C. Six-month outcome was poor in 47 (60.3%) patients. The DIA-MS analysis identified and quantified 403 unique human proteins. Differential protein abundance testing comparing poor to good outcome showed 19 elevated proteins in patients with poor outcome (log2-fold change (FC) range 0.28-1.17) and 16 reduced proteins (log2(FC) between - 0.22 and - 0.68), involved in inflammatory/immune responses and apoptotic signalling pathways for poor outcome and proteolysis for good outcome. Analysis according to level of TTM showed a significant protein abundance difference for six proteins [five elevated proteins in TTM 36 °C (log2(FC) between 0.33 and 0.88), one reduced protein (log2(FC) - 0.6)] mainly involved in inflammatory/immune responses only at 48 h after cardiac arrest. CONCLUSIONS: Serum proteome profiling revealed an increase in inflammatory/immune responses and apoptosis in patients with poor outcome. In patients with good outcome, an increase in proteolysis was observed, whereas TTM-level only had a modest effect on the proteome profiles. Further validation of the differentially abundant proteins in response to neurological outcome is necessary to validate novel biomarker candidates that may predict prognosis after cardiac arrest.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

External validation of the CREST model to predict early circulatory-etiology death after out-of-hospital cardiac arrest without initial ST-segment elevation myocardial infarction.

BACKGROUND: The CREST model is a prediction model, quantitating the risk of circulatory-etiology death (CED) after cardiac arrest based on variables available at hospital admission, and intend to guide the triage of comatose patients without ST-segment-elevation myocardial infarction after successful cardiopulmonary resuscitation. This study assessed performance of the CREST model in the Target Temperature Management (TTM) trial cohort. METHODS: We retrospectively analyzed data from resuscitated out-of-hospital cardiac arrest (OHCA) patients in the TTM-trial. Demographics, clinical characteristics, and CREST variables (history of coronary artery disease, initial heart rhythm, initial ejection fraction, shock at admission and ischemic time > 25 min) were assessed in univariate and multivariable analysis. The primary outcome was CED. The discriminatory power of the logistic regression model was assessed using the C-statistic and goodness of fit was tested according to Hosmer-Lemeshow. RESULTS: Among 329 patients eligible for final analysis, 71 (22%) had CED. History of ischemic heart disease, previous arrhythmia, older age, initial non-shockable rhythm, shock at admission, ischemic time > 25 min and severe left ventricular dysfunction were variables associated with CED in univariate analysis. CREST variables were entered into a logistic regression model and the area under the curve for the model was 0.73 with adequate calibration according to Hosmer-Lemeshow test (p = 0.602). CONCLUSIONS: The CREST model had good validity and a discrimination capability for predicting circulatory-etiology death after resuscitation from cardiac arrest without ST-segment elevation myocardial infarction. Application of this model could help to triage high-risk patients for transfer to specialized cardiac centers.

Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial.

INTRODUCTION: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care. METHODS AND ANALYSIS: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation. ETHICS AND DISSEMINATION: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05249088.

Intensive care unit burden is associated with increased mortality in critically ill COVID-19 patients.

BACKGROUND: Traditional models to predict intensive care outcomes do not perform well in COVID-19. We undertook a comprehensive study of factors affecting mortality and functional outcome after severe COVID-19. METHODS: In this prospective multicentre cohort study, we enrolled laboratory-confirmed, critically ill COVID-19 patients at six ICUs in the Skåne Region, Sweden, between May 11, 2020, and May 10, 2021. Demographics and clinical data were collected. ICU burden was defined as the total number of ICU-treated COVID-19 patients in the region on admission. Surviving patients had a follow-up at 90 days for assessment of functional outcome using the Glasgow Outcome Scale-Extended (GOSE), an ordinal scale (1-8) with GOSE ≥5 representing a favourable outcome. The primary outcome was 90-day mortality; the secondary outcome was functional outcome at 90 days. RESULTS: Among 498 included patients, 74% were male with a median age of 66 years and a median body mass index (BMI) of 30 kg/m2 . Invasive mechanical ventilation was employed in 72%. Mortality in the ICU, in-hospital and at 90 days was 30%, 38% and 39%, respectively. Mortality increased markedly at age 60 and older. Increasing ICU burden was independently associated with a two-fold increase in mortality. Higher BMI was not associated with increased mortality. Besides age and ICU burden, smoking status, cortisone use, Pa CO2 >7 kPa, and inflammatory markers on admission were independent factors of 90-day mortality. Lower GOSE at 90 days was associated with a longer stay in the ICU. CONCLUSION: In critically ill COVID-19 patients, the 90-day mortality was 39% and increased considerably at age 60 or older. The ICU burden was associated with mortality, whereas a high BMI was not. A longer stay in the ICU was associated with unfavourable functional outcomes at 90 days.

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial.

BACKGROUND: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. METHODS: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). RESULTS: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). CONCLUSIONS: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial.

BACKGROUND: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients' outcome. METHODS: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. RESULTS: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93-1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95-1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003). CONCLUSIONS: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. TRIAL REGISTRATION: clinicaltrials.gov NCT02908308 , Registered September 20, 2016.

Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest.

Title: Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest. Background: Out-of-hospital cardiac arrest (OHCA) survivors generally report good health-related quality of life, but physical aspects of health seem more affected than other domains. Limitations in physical function after surviving OHCA have received little attention. Aims: To describe physical function 6 months after OHCA and compare it with a group of ST elevation myocardial infarction (STEMI) controls, matched for country, age, sex and time of the cardiac event. A second aim was to explore variables potentially associated with self-reported limitations in physical function in OHCA survivors. Methods: A cross-sectional sub-study of the Targeted Temperature Management at 33 °C versus 36 °C (TTM) trial with a follow-up 6 months post-event. Physical function was the main outcome assessed with the self-reported Physical Functioning-10 items scale (PF-10). PF-10 is presented as T-scores (0-100), where 50 represents the norm mean. Scores <47 at a group level, or <45 at an individual level indicate limitations in physical function. Results: 287 OHCA survivors and 119 STEMI controls participated. Self-reported physical function by PF-10 was significantly lower for OHCA survivors compared to STEMI controls (mean 46.0, SD 11.2 vs. 48.8, SD 9.0, p = 0.025). 38% of OHCA survivors compared to 26% of STEMI controls reported limitations in physical function at an individual level (p = 0.022). The most predictive variables for self-reported limitations in physical function in OHCA survivors were older age, female sex, cognitive impairment, and symptoms of anxiety and depression after 6 months. Conclusion: Self-reported limitations in physical function are more common in OHCA survivors compared to STEMI controls. Trial registration: ClinicalTrials.gov Identifier: NCT01946932.

Cognitive Behavioral Therapy and Acceptance and Commitment Therapy (CBT-ACT) vs. Standard Care After Critical Illness Due to COVID-19: Protocol for a Pilot Randomized Controlled Trial.

Background: Post-covid syndrome is an emerging condition involving a wide range of symptoms, including high rates of poor mental health. The diagnostic relevance and clinical severity of these symptoms are largely unknown, and evidence for treatment of post-covid mental health symptoms is lacking. This protocol describes a pilot randomized clinical trial, primarily aiming to assess feasibility, participant adherence and satisfaction in a novel phycho-therapeutic intervention on post-covid anxiety and depression symptoms ≥1 year after critically ill COVID-19. Whether the intervention may generate improvements in post-covid depression, anxiety, post-traumatic stress and health-related quality of life (HRQoL) will be addressed in a following larger trial. Methods: A multicenter, investigator-initiated randomized controlled trial (Clinical Trial Identifier number NCT05119608) including Intensive Care Unit (ICU)-treated COVID-19 survivors, who display symptoms of anxiety and/or depression at follow-up 12 months after hospitalization (Hospital Anxiety and Depression Scale ≥8 for depression or anxiety). Eligible individuals are referred to a psychiatrist for structured diagnostic assessment and inclusion in the trial. Participants will be randomized to either a 10-week cognitive behavioral therapy intervention with added acceptance and commitment therapy (CBT-ACT) or standard care (primary care referral). Primary study outcome measure is feasibility and patient adherence, defined as the proportion of participants who consent to randomization and remain in the study including follow-up. Secondary outcome measures include reduced symptoms in the HADS depression/anxiety subscales, post-traumatic symptoms, HRQoL and user satisfaction at 3 months after the intervention. Discussion: This protocol describes a pilot trial to assess feasibility and preliminary effects of a structured psycho-therapeutic intervention to ameliorate mental health in a population severely affected by COVID-19, where evidence for structured psycho-therapy is lacking.

Is frailty associated with long-term survival, neurological function and patient-reported outcomes after in-hospital cardiac arrest? - A Swedish cohort study.

BACKGROUND: Frailty is associated with poor 30-days survival after in-hospital cardiac arrests (IHCA). The aim was to assess how pre-arrest frailty was associated with long-term survival, neurological function and patient-reported outcomes in elderly survivors after IHCA. METHODS: Patients aged ≥ 65 years with IHCA at Karolinska University Hospital between 2013-2021 were studied. Frailty was assessed by the Clinical Frailty Scale (CFS) based on clinical records and categorised into non-frail (1-4) or frail (5-7). Survival was assessed in days. Neurological function was assessed by the Cerebral Performance Category scale (CPC). A telephone interview was performed six months post-IHCA and included the questionnaires EuroQoL-5 Dimensions-5 Levels and Hospital Anxiety and Depression Scale. RESULTS: Totally, 232 (28%) out of 817 eligible patients survived to 30-days. Out of 232, 65 (28%) were frail. Long-term survival was better for non-frail than frail patients (6 months (92% versus 75%, p-value < 0.01), 3 years (74% vs 22%, p-value < 0.01)). The vast majority of both non-frail and frail patients had unchanged CPC from admittance to discharge from hospital (87% and 85%, respectively, p-value 0.52). The 121 non-frail patients reported better health compared to 27 frail patients (EQ-VAS median 70 versus 50 points, p-value < 0.01) and less symptoms of depression than frail (16% and 52%, respectively, p-value < 0.01). CONCLUSION: Frail patients suffering IHCA survived with the same neurological function they had at admittance. Although one in five frail patients survived to three years, frailty was associated with a marked decrease in long-term survival as well as increased symptoms of depression and poorer general health.

Differences in self-reported health between cardiac arrest survivors with good cerebral performance and survivors with moderate cerebral disability: a nationwide register study.

OBJECTIVE: The aim was to compare self-reported health between cardiac arrest survivors with good cerebral performance (CPC 1) and survivors with moderate cerebral disability (CPC 2). METHODS: This comparative register study was based on nationwide data from the Swedish Register of Cardiopulmonary Resuscitation. The study included 2058 in-hospital and out-of-hospital cardiac arrest survivors with good cerebral performance or survivors with moderate cerebral disability, 3-6 months postcardiac arrest. Survivors completed a questionnaire including the Hospital Anxiety and Depression Scale (HADS) and EQ-5D five-levels (EQ-5D-5L). Data were analysed using ordinal and linear regression models. RESULTS: For all survivors, the prevalence of anxiety and depression symptoms measured by the HADS was 14% and 13%, respectively. Using the EQ-5D-5L, the cardiac arrest survivors reported most health problems relating to pain/discomfort (57%), followed by anxiety/depression (47%), usual activities (46%), mobility (40%) and self-care (18%). Compared with the survivors with good cerebral performance, survivors with moderate cerebral disability reported significantly higher symptom levels of anxiety and depression measured with HADS, and poorer health in all dimensions of the EQ-5D-5L after adjusting for age, sex, place of cardiac arrest, aetiology and initial rhythm (p<0.001). CONCLUSIONS: These findings stress the importance of screening for health problems in all cardiac arrest survivors to identify those in need of professional support and rehabilitation, independent on neurological outcome.

Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial.

PURPOSE: The optimal ventilatory settings in patients after cardiac arrest and their association with outcome remain unclear. The aim of this study was to describe the ventilatory settings applied in the first 72 h of mechanical ventilation in patients after out-of-hospital cardiac arrest and their association with 6-month outcomes. METHODS: Preplanned sub-analysis of the Target Temperature Management-2 trial. Clinical outcomes were mortality and functional status (assessed by the Modified Rankin Scale) 6 months after randomization. RESULTS: A total of 1848 patients were included (mean age 64 [Standard Deviation, SD = 14] years). At 6 months, 950 (51%) patients were alive and 898 (49%) were dead. Median tidal volume (VT) was 7 (Interquartile range, IQR = 6.2-8.5) mL per Predicted Body Weight (PBW), positive end expiratory pressure (PEEP) was 7 (IQR = 5-9) cmH20, plateau pressure was 20 cmH20 (IQR = 17-23), driving pressure was 12 cmH20 (IQR = 10-15), mechanical power 16.2 J/min (IQR = 12.1-21.8), ventilatory ratio was 1.27 (IQR = 1.04-1.6), and respiratory rate was 17 breaths/minute (IQR = 14-20). Median partial pressure of oxygen was 87 mmHg (IQR = 75-105), and partial pressure of carbon dioxide was 40.5 mmHg (IQR = 36-45.7). Respiratory rate, driving pressure, and mechanical power were independently associated with 6-month mortality (omnibus p-values for their non-linear trajectories: p < 0.0001, p = 0.026, and p = 0.029, respectively). Respiratory rate and driving pressure were also independently associated with poor neurological outcome (odds ratio, OR = 1.035, 95% confidence interval, CI = 1.003-1.068, p = 0.030, and OR = 1.005, 95% CI = 1.001-1.036, p = 0.048). A composite formula calculated as [(4*driving pressure) + respiratory rate] was independently associated with mortality and poor neurological outcome. CONCLUSIONS: Protective ventilation strategies are commonly applied in patients after cardiac arrest. Ventilator settings in the first 72 h after hospital admission, in particular driving pressure and respiratory rate, may influence 6-month outcomes.

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators.

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Serum neurofilament light levels are correlated to long-term neurocognitive outcome measures after cardiac arrest.

OBJECTIVE: To explore associations between four methods assessing long-term neurocognitive outcome after out-of-hospital cardiac arrest and early hypoxic-ischemic neuronal brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the outcome methods. METHODS: An explorative post-hoc study was conducted on survivor data from the international Target Temperature Management after Out-of-hospital Cardiac Arrest trial, investigating serum NFL sampled 48/72-hours post-arrest and neurocognitive outcome 6 months post-arrest. RESULTS: Among the long-term surviving participants (N = 457), serum NFL (n = 384) was associated to all outcome instruments, also when controlling for demographic and cardiovascular risk factors. Associations between NFL and the patient-reported Two Simple Questions (TSQ) were however attenuated when adjusting for vitality and mental health. NFL predicted results on the outcome instruments to varying degrees, with an excellent area under the curve for the clinician-report Cerebral Performance Category (CPC 1-2: 0.90). Most participants were classified as CPC 1 (79%). Outcome instrument correlations ranged from small (Mini-Mental State Examination [MMSE]-TSQ) to strong (CPC-MMSE). CONCLUSIONS: The clinician-reported CPC was mostly related to hypoxic-ischemic brain injury, but with a ceiling effect. These results may be useful when selecting methods and instruments for clinical follow-up models.