2021 European Resuscitation Council/European Society of Intensive Care Medicine Algorithm for Prognostication of Poor Neurological Outcome After Cardiac Arrest-Can Entry Criteria Be Broadened?

OBJECTIVES: To explore broadened entry criteria of the 2021 European Resuscitation Council/European Society of Intensive Care Medicine (ERC/ESICM) algorithm for neuroprognostication including patients with ongoing sedation and Glasgow Coma Scale-Motor score (GCS-M) scores 4-5. DESIGN: Retrospective multicenter observational study. SETTING: Four ICUs, Skane, Sweden. PATIENTS: Postcardiac arrest patients managed at targeted temperature 36°C, 2014-2018. Neurologic outcome was assessed after 2-6 months according to the Cerebral Performance Category scale. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In 794 included patients, median age was 69.5 years (interquartile range, 60.6-77.0 yr), 241 (30.4%) were female, 550 (69.3%) had an out-of-hospital cardiac arrest, and 314 (41.3%) had a shockable rhythm. Four hundred ninety-five patients were dead at follow-up, 330 of 495 died after a decision on withdrawal of life-sustaining therapies. At 72 hours after cardiac arrest 218 patients remained unconscious. The entry criteria of the original algorithm (GCS-M 1-3) was fulfilled by 163 patients and 115 patients with poor outcome were identified, with false positive rate (FPR) of 0% (95% CI, 0-79.4%) and sensitivity of 71.0% (95% CI, 63.6-77.4%). Inclusion of patients with ongoing sedation identified another 13 patients with poor outcome, generating FPR of 0% (95% CI, 0-65.8%) and sensitivity of 69.6% (95% CI, 62.6-75.8%). Inclusion of all unconscious patients (GCS-M 1-5), regardless of sedation, identified one additional patient, generating FPR of 0% (95% CI, 0-22.8) and sensitivity of 62.9% (95% CI, 56.1-69.2). The few patients with true negative prediction (patients with good outcome not fulfilling guideline criteria of a poor outcome) generated wide 95% CI for FPR. CONCLUSION: The 2021 ERC/ESICM algorithm for neuroprognostication predicted poor neurologic outcome with a FPR of 0%. Broadening inclusion criteria to include all unconscious patients regardless of ongoing sedation identified an additional small number of patients with poor outcome but did not affect the FPR. Results are limited by high rate of withdrawal of life-sustaining therapies and few patients with true negative prediction.

Plasma glial fibrillary acidic protein and tau: predictors of neurological outcome after cardiac arrest.

BACKGROUND: The purpose was to evaluate glial fibrillary acidic protein (GFAP) and total-tau in plasma as predictors of poor neurological outcome after out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA), including comparisons with neurofilament light (NFL) and neuron-specific enolase (NSE). METHODS: Retrospective multicentre observational study of patients admitted to an intensive care unit (ICU) in three hospitals in Sweden 2014-2018. Blood samples were collected at ICU admission, 12 h, and 48 h post-cardiac arrest. Poor neurological outcome was defined as Cerebral Performance Category 3-5 at 2-6 months after cardiac arrest. Plasma samples were retrospectively analysed for GFAP, tau, and NFL. Serum NSE was analysed in clinical care. Prognostic performances were tested with the area under the receiver operating characteristics curve (AUC). RESULTS: Of the 428 included patients, 328 were OHCA, and 100 were IHCA. At ICU admission, 12 h and 48 h post-cardiac arrest, GFAP predicted neurological outcome after OHCA with AUC (95% CI) 0.76 (0.70-0.82), 0.86 (0.81-0.90) and 0.91 (0.87-0.96), and after IHCA with AUC (95% CI) 0.77 (0.66-0.87), 0.83 (0.74-0.92) and 0.83 (0.71-0.95). At the same time points, tau predicted outcome after OHCA with AUC (95% CI) 0.72 (0.66-0.79), 0.75 (0.69-0.81), and 0.93 (0.89-0.96) and after IHCA with AUC (95% CI) 0.61 (0.49-0.74), 0.68 (0.56-0.79), and 0.77 (0.65-0.90). Adding the change in biomarker levels between time points did not improve predictive accuracy compared to the last time point. In a subset of patients, GFAP at 12 h and 48 h, as well as tau at 48 h, offered similar predictive value as NSE at 48 h (the earliest time point NSE is recommended in guidelines) after both OHCA and IHCA. The predictive performance of NFL was similar or superior to GFAP and tau at all time points after OHCA and IHCA. CONCLUSION: GFAP and tau are promising biomarkers for neuroprognostication, with the highest predictive performance at 48 h after OHCA, but not superior to NFL. The predictive ability of GFAP may be sufficiently high for clinical use at 12 h after cardiac arrest.

Plasma neurofilament light is a predictor of neurological outcome 12 h after cardiac arrest.

BACKGROUND: Previous studies have reported high prognostic accuracy of circulating neurofilament light (NfL) at 24-72 h after out-of-hospital cardiac arrest (OHCA), but performance at earlier time points and after in-hospital cardiac arrest (IHCA) is less investigated. We aimed to assess plasma NfL during the first 48 h after OHCA and IHCA to predict long-term outcomes. METHODS: Observational multicentre cohort study in adults admitted to intensive care after cardiac arrest. NfL was retrospectively analysed in plasma collected on admission to intensive care, 12 and 48 h after cardiac arrest. The outcome was assessed at two to six months using the Cerebral Performance Category (CPC) scale, where CPC 1-2 was considered a good outcome and CPC 3-5 a poor outcome. Predictive performance was measured with the area under the receiver operating characteristic curve (AUROC). RESULTS: Of 428 patients, 328 (77%) suffered OHCA and 100 (23%) IHCA. Poor outcome was found in 68% of OHCA and 55% of IHCA patients. The overall prognostic performance of NfL was excellent at 12 and 48 h after OHCA, with AUROCs of 0.93 and 0.97, respectively. The predictive ability was lower after IHCA than OHCA at 12 and 48 h, with AUROCs of 0.81 and 0.86 (p ≤ 0.03). AUROCs on admission were 0.77 and 0.67 after OHCA and IHCA, respectively. At 12 and 48 h after OHCA, high NfL levels predicted poor outcome at 95% specificity with 70 and 89% sensitivity, while low NfL levels predicted good outcome at 95% sensitivity with 71 and 74% specificity and negative predictive values of 86 and 88%. CONCLUSIONS: The prognostic accuracy of NfL for predicting good and poor outcomes is excellent as early as 12 h after OHCA. NfL is less reliable for the prediction of outcome after IHCA.

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.

Retrograde cerebral perfusion reduces embolic and watershed lesions after acute type a aortic dissection repair with deep hypothermic circulatory arrest.

BACKGROUND: To assess whether retrograde cerebral perfusion reduces neurological injury and mortality in patients undergoing surgery for acute type A aortic dissection. METHODS: Single-center, retrospective, observational study including all patients undergoing acute type A aortic dissection repair with deep hypothermic circulatory arrest between January 1998 and December 2022 with or without the adjunct of retrograde cerebral perfusion. 515 patients were included: 257 patients with hypothermic circulatory arrest only and 258 patients with hypothermic circulatory arrest and retrograde cerebral perfusion. The primary endpoints were clinical neurological injury, embolic lesions, and watershed lesions. Multivariable logistic regression was performed to identify independent predictors of the primary outcomes. Survival analysis was performed using Kaplan-Meier estimates. RESULTS: Clinical neurological injury and embolic lesions were less frequent in patients with retrograde cerebral perfusion (20.2% vs. 28.4%, p = 0.041 and 13.7% vs. 23.4%, p = 0.010, respectively), but there was no significant difference in the occurrence of watershed lesions (3.0% vs. 6.1%, p = 0.156). However, after multivariable logistic regression, retrograde cerebral perfusion was associated with a significant reduction of clinical neurological injury (OR: 0.60; 95% CI 0.36-0.995, p = 0.049), embolic lesions (OR: 0.55; 95% CI 0.31-0.97, p = 0.041), and watershed lesions (OR: 0.25; 95%CI 0.07-0.80, p = 0.027). There was no significant difference in 30-day mortality (12.8% vs. 11.7%, p = ns) or long-term survival between groups. CONCLUSION: In this study, we showed that the addition of retrograde cerebral perfusion during hypothermic circulatory arrest in the setting of acute type A aortic dissection repair reduced the risk of clinical neurological injury, embolic lesions, and watershed lesions.

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.

Regional Brain Net Water Uptake in Computed Tomography after Cardiac Arrest - A Novel Biomarker for Neuroprognostication.

BACKGROUND: Selective water uptake by neurons and glial cells and subsequent brain tissue oedema are key pathophysiological processes of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). Although brain computed tomography (CT) is widely used to assess the severity of HIE, changes of brain radiodensity over time have not been investigated. These could be used to quantify regional brain net water uptake (NWU), a potential prognostic biomarker. METHODS: We conducted an observational prognostic accuracy study including a derivation (single center cardiac arrest registry) and a validation (international multicenter TTM2 trial) cohort. Early (<6 h) and follow-up (>24 h) head CTs of CA patients were used to determine regional NWU for grey and white matter regions after co-registration with a brain atlas. Neurological outcome was dichotomized as good versus poor using the Cerebral Performance Category Scale (CPC) in the derivation cohort and Modified Rankin Scale (mRS) in the validation cohort. RESULTS: We included 115 patients (81 derivation, 34 validation) with out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA). Regional brain water content remained unchanged in patients with good outcome. In patients with poor neurological outcome, we found considerable regional water uptake with the strongest effect in the basal ganglia. NWU >8% in the putamen and caudate nucleus predicted poor outcome with 100% specificity (95%-CI: 86-100%) and 43% (moderate) sensitivity (95%-CI: 31-56%). CONCLUSION: This pilot study indicates that NWU derived from serial head CTs is a promising novel biomarker for outcome prediction after CA. NWU >8% in basal ganglia grey matter regions predicted poor outcome while absence of NWU indicated good outcome. NWU and follow-up CTs should be investigated in larger, prospective trials with standardized CT acquisition protocols.

Standardised and automated assessment of head computed tomography reliably predicts poor functional outcome after cardiac arrest: a prospective multicentre study.

PURPOSE: Application of standardised and automated assessments of head computed tomography (CT) for neuroprognostication after out-of-hospital cardiac arrest. METHODS: Prospective, international, multicentre, observational study within the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Routine CTs from adult unconscious patients obtained > 48 h ≤ 7 days post-arrest were assessed qualitatively and quantitatively by seven international raters blinded to clinical information using a pre-published protocol. Grey-white-matter ratio (GWR) was calculated from four (GWR-4) and eight (GWR-8) regions of interest manually placed at the basal ganglia level. Additionally, GWR was obtained using an automated atlas-based approach. Prognostic accuracies for prediction of poor functional outcome (modified Rankin Scale 4-6) for the qualitative assessment and for the pre-defined GWR cutoff < 1.10 were calculated. RESULTS: 140 unconscious patients were included; median age was 68 years (interquartile range [IQR] 59-76), 76% were male, and 75% had poor outcome. Standardised qualitative assessment and all GWR models predicted poor outcome with 100% specificity (95% confidence interval [CI] 90-100). Sensitivity in median was 37% for the standardised qualitative assessment, 39% for GWR-8, 30% for GWR-4 and 41% for automated GWR. GWR-8 was superior to GWR-4 regarding prognostic accuracies, intra- and interrater agreement. Overall prognostic accuracy for automated GWR (area under the curve [AUC] 0.84, 95% CI 0.77-0.91) did not significantly differ from manually obtained GWR. CONCLUSION: Standardised qualitative and quantitative assessments of CT are reliable and feasible methods to predict poor functional outcome after cardiac arrest. Automated GWR has the potential to make CT quantification for neuroprognostication accessible to all centres treating cardiac arrest patients.

Hypothermia versus normothermia after out-of-hospital cardiac arrest; the effect on post-intervention serum concentrations of sedatives and analgesics and time to awakening.

BACKGROUND: This study investigated the association of two levels of targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) with administered doses of sedative and analgesic drugs, serum concentrations, and the effect on time to awakening. METHODS: This substudy of the TTM2-trial was conducted at three centers in Sweden, with patients randomized to either hypothermia or normothermia. Deep sedation was mandatory during the 40-hour intervention. Blood samples were collected at the end of TTM and end of protocolized fever prevention (72 hours). Samples were analysed for concentrations of propofol, midazolam, clonidine, dexmedetomidine, morphine, oxycodone, ketamine and esketamine. Cumulative doses of administered sedative and analgesic drugs were recorded. RESULTS: Seventy-one patients were alive at 40 hours and had received the TTM-intervention according to protocol. 33 patients were treated at hypothermia and 38 at normothermia. There were no differences between cumulative doses and concentration and of sedatives/analgesics between the intervention groups at any timepoint. Time until awakening was 53 hours in the hypothermia group compared to 46 hours in the normothermia group (p = 0.09). CONCLUSION: This study of OHCA patients treated at normothermia versus hypothermia found no significant differences in dosing or concentration of sedatives or analgesic drugs in blood samples drawn at the end of the TTM intervention, or at end of protocolized fever prevention, nor the time to awakening.

S100B predicts neurological injury and 30-day mortality following surgery for acute type A aortic dissection: an observational cohort study.

BACKGROUND: Neurological injuries are frequent following Acute Type A Aortic Dissection (ATAAD) repair occurring in 4-30% of all patients. Our objective was to study whether S100B can predict neurological injury following ATAAD repair. METHODS: This was a single-center, retrospective, observational study. The study included all patients that underwent ATAAD repair at our institution between Jan 1998 and Dec 2021 and had recorded S100B-values. The primary outcome measure was neurological injury, defined as focal neurological deficit or coma diagnosed by clinical assessment with or without radiological confirmation and with a symptom duration of more than 24 h. Secondary outcome measure was 30-day mortality. RESULTS: 538 patients underwent surgery during the study period and 393 patients, had recorded S100B-values. The patients had a mean age of 64.4 ± 11.1 years and 34% were female. Receiver operating characteristic curve for S100B 24 h postoperatively yielded area under the curve 0.687 (95% CI 0.615-0.759) and best Youden's index corresponded to S100B 0.225 which gave a sensitivity of 60% and specificity of 75%. Multivariable logistic regression identified S100B ≥ 0.23 µg/l at 24 h as an independent predictor for neurological injury (OR 4.71, 95% CI 2.59-8.57; p < 0.01) along with preoperative cerebral malperfusion (OR 4.23, 95% CI 2.03-8.84; p < 0.01) as well as an independent predictor for 30-day mortality (OR 4.57, 95% CI 1.18-11.70; p < 0.01). CONCLUSIONS: We demonstrated that S100B, 24 h after surgery is a strong independent predictor for neurological injury and 30-day mortality after ATAAD repair. TRIAL REGISTRATION: As this was a retrospective observational study it was not registered.

Radiological properties of neurological injury following acute type A aortic dissection repair.

Objective: The study objective was to assess the radiological properties of acute type A aortic dissection-related neurological injuries and identify predictors of neurological injury. Methods: Our single-center, retrospective, observational study included all patients who underwent acute type A aortic dissection repair between January 1998 and December 2021. Multivariable analyses and Cox regression were performed to identify predictors of embolic lesions, watershed lesions, neurological injury, 30-day mortality, and late mortality. Results: A total of 538 patients were included. Of these, 120 patients (22.3%) experienced postoperative neurological injury; 74 patients (13.8%) had postoperative stroke, and 36 patients (6.8%) had postoperative coma. The 30-day mortality was 22.7% in the neurological injury group versus 5.8% in the no neurological injury group (P < .001). We identified several independent predictors of neurological injury. Cerebral malperfusion (odds ratio, 2.77; 95% confidence interval, 1.53-5.00), systemic hypotensive shock (odds ratio, 1.97; 95% confidence interval, 1.13-3.43), and aortic arch replacement (odds ratio, 3.08; 95% confidence interval, 1.17-8.08) predicted embolic lesions. Diabetes mellitus (odds ratio, 5.35; 95% confidence interval, 1.85-15.42), previous cardiac surgery (odds ratio, 8.62; 95% confidence interval, 1.47-50.43), duration of hypothermic circulatory arrest (odds ratio, 1.05; 95% confidence interval, 1.01-1.08), cardiopulmonary bypass time (odds ratio, 1.01; 95% confidence interval, 1.00-1.01), ascending aortic/arch cannulation (odds ratio, 5.68; 95% confidence interval, 1.88-17.12), and left ventricular cannulation (odds ratio, 17.81; 95% confidence interval, 1.69-188.01) predicted watershed lesions. Retrograde cerebral perfusion (odds ratio, 0.28; 95% confidence interval, 0.01-0.84) had a protective effect against watershed lesions. Conclusions: In this study, we demonstrated that the radiological features of neurological injury may be as important as clinical characteristics in understanding the pathophysiology and causality behind neurological injury related to acute type A aortic dissection repair.

Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest.

Importance: Blood phosphorylated tau (p-tau) and amyloid-ß peptides (Aß) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. Objective: To evaluate whether the levels and trajectories of blood p-tau, Aß42, and Aß40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. Design, Setting, and Participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aß42, and Aß40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. Exposures: Serum p-tau, Aß42, and Aß40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. Main Outcomes and Measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aß42 and Aß40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. Conclusions and Relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aß peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

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.

Carbon dioxide flooding to reduce postoperative neurological injury following surgery for acute type A aortic dissection: a prospective, randomised, blinded, controlled clinical trial, CARTA study protocol - objectives and design.

INTRODUCTION: Neurological complications after surgery for acute type A aortic dissection (ATAAD) increase patient morbidity and mortality. Carbon dioxide flooding is commonly used in open-heart surgery to reduce the risk of air embolism and neurological impairment, but it has not been evaluated in the setting of ATAAD surgery. This report describes the objectives and design of the CARTA trial, investigating whether carbon dioxide flooding reduces neurological injury following surgery for ATAAD. METHODS AND ANALYSIS: The CARTA trial is a single-centre, prospective, randomised, blinded, controlled clinical trial of ATAAD surgery with carbon dioxide flooding of the surgical field. Eighty consecutive patients undergoing repair of ATAAD, and who do not have previous neurological injuries or ongoing neurological symptoms, will be randomised (1:1) to either receive carbon dioxide flooding of the surgical field or not. Routine repair will be performed regardless of the intervention. The primary endpoints are size and number of ischaemic lesions on brain MRI performed after surgery. Secondary endpoints are clinical neurological deficit according to the National Institutes of Health Stroke Scale, level of consciousness using the Glasgow Coma Scale motor score, brain injury markers in blood after surgery, neurological function according to the modified Rankin Scale and postoperative recovery 3 months after surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Swedish Ethical Review Agency for this study. Results will be disseminated through peer-reviewed media. TRIAL REGISTRATION NUMBER: NCT04962646.

Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest.

BACKGROUND/AIM: Signs of hypoxic ischaemic encephalopathy (HIE) on head computed tomography (CT) predicts poor neurological outcome after cardiac arrest. We explore whether levels of brain injury markers in blood could predict the likelihood of HIE on CT. METHODS: Retrospective analysis of CT performed at 24-168 h post cardiac arrest on clinical indication within the Target Temperature Management after out-of-hospital cardiac arrest-trial. Biomarkers prospectively collected at 24- and 48 h post-arrest were analysed for neuron specific enolase (NSE), neurofilament light (NFL), total-tau and glial fibrillary acidic protein (GFAP). HIE was assessed through visual evaluation and quantitative grey-white-matter ratio (GWR) was retrospectively calculated on Swedish subjects with original images available. RESULTS: In total, 95 patients were included. The performance to predict HIE on CT (performed at IQR 73-116 h) at 48 h was similar for all biomarkers, assessed as area under the receiving operating characteristic curve (AUC) NSE 0.82 (0.71-0.94), NFL 0.79 (0.67-0.91), total-tau 0.84 (0.74-0.95), GFAP 0.79 (0.67-0.90). The predictive performance of biomarker levels at 24 h was AUC 0.72-0.81. At 48 h biomarker levels below Youden Index accurately excluded HIE in 77.3-91.7% (negative predictive value) and levels above Youden Index correctly predicted HIE in 73.3-83.7% (positive predictive value). NSE cut-off at 48 h was 48 ng/ml. Elevated biomarker levels irrespective of timepoint significantly correlated with lower GWR. CONCLUSION: Biomarker levels can assess the likelihood of a patient presenting with HIE on CT and could be used to select suitable patients for CT-examination during neurological prognostication in unconscious cardiac arrest patients.

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.

A pilot study of methods for prediction of poor outcome by head computed tomography after cardiac arrest.

INTRODUCTION: In Sweden, head computed tomography (CT) is commonly used for prediction of neurological outcome after cardiac arrest, as recommended by guidelines. We compare the prognostic ability and interrater variability of routine and novel CT methods for prediction of poor outcome. METHODS: Retrospective study including patients from Swedish sites within the Target Temperature Management after out-of-hospital cardiac arrest trial examined with CT. Original images were assessed by two independent radiologists blinded from clinical data with eye-balling without pre-specified criteria, and with a semi-quantitative assessment. Grey-white-matter ratios (GWR) were quantified using models with 4-20 manually placed regions of interest. Prognostic abilities and interrater variability were calculated for prediction of poor outcome (modified Rankin Scale 4-6 at 6 months) for early (<24 h) and late (≥24 h) examinations. RESULTS: 68/106 (64 %) of included patients were examined < 24 h post-arrest. Eye-balling predicted poor outcome with 89-100 % specificity and 15-78 % sensitivity. GWR < 24 h predicted neurological outcome with unsatisfactory to satisfactory Area Under the Receiver Operating Characteristics Curve (AUROC: 0.54-0.64). GWR ≥ 24 h yielded very good to excellent AUROC (0.80-0.93). Sensitivities increased > 2-3-fold in examinations performed after 24 h compared to early examinations. Combining eye-balling with GWR < 1.15 predicted poor outcome without false positives with sensitivities remaining acceptable. CONCLUSION: In our cohort, qualitative and quantitative CT methods predicted poor outcome with high specificity and low to moderate sensitivity. Sensitivity increased relevantly after the first 24 h after CA. Interrater variability poses a problem and indicates the need to standardise brain CT evaluation to increase the methods' safety.

Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial.

BACKGROUND AND OBJECTIVES: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL. METHODS: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used. RESULTS: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels (p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R2 = 0.30 and R2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous. DISCUSSION: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT01020916.

Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy.

Background: Head computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA. Methods/design: This is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely examined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of "severe HIE". Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0-3) and poor (modified Rankin Scale 4-6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and specificities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter- and intra-rater reliabilities according to STARD guidelines. Conclusions: The results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients.The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065.

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.