Neurofilament light as an outcome predictor after cardiac arrest: a post hoc analysis of the COMACARE trial.
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ABSTRACT: Purpose
Neurofilament light (NfL) is a biomarker reflecting neurodegeneration and acute neuronal injury, and an increase is found following hypoxic brain damage. We assessed the ability of plasma NfL to predict outcome in comatose patients after out-of-hospital cardiac arrest (OHCA). We also compared plasma NfL concentrations between patients treated with two different targets of arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), and mean arterial pressure (MAP).Methods
We measured NfL concentrations in plasma obtained at intensive care unit admission and at 24, 48, and 72 h after OHCA. We assessed neurological outcome at 6 months and defined a good outcome as Cerebral Performance Category (CPC) 1-2 and poor outcome as CPC 3-5.Results
Six-month outcome was good in 73/112 (65%) patients. Forty-eight hours after OHCA, the median NfL concentration was 19 (interquartile range [IQR] 11-31) pg/ml in patients with good outcome and 2343 (587-5829) pg/ml in those with poor outcome, p < 0.001. NfL predicted poor outcome with an area under the receiver operating characteristic curve (AUROC) of 0.98 (95% confidence interval [CI] 0.97-1.00) at 24 h, 0.98 (0.97-1.00) at 48 h, and 0.98 (0.95-1.00) at 72 h. NfL concentrations were lower in the higher MAP (80-100 mmHg) group than in the lower MAP (65-75 mmHg) group at 48 h (median, 23 vs. 43 pg/ml, p = 0.04). PaCO2 and PaO2 targets did not associate with NfL levels.Conclusions
NfL demonstrated excellent prognostic accuracy after OHCA. Higher MAP was associated with lower NfL concentrations.
SUBMITTER: Wihersaari L
PROVIDER: S-EPMC7782453 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectivesEEG 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.MethodsWe 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.ResultsA 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.DiscussionBenign, 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 informationClinicalTrials.gov NCT01020916.
| S-EPMC9231840 | biostudies-literature
Project description:BackgroundPrevious 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.MethodsObservational 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).ResultsOf 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%.ConclusionsThe 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.
| S-EPMC9960417 | biostudies-literature
Project description:ImportancePrognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units.ObjectiveTo determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest.Design, setting and participantsProspective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible.ExposuresSerum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay.Main outcomes and measuresPoor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death).ResultsOf 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P < .001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level).Conclusions and relevanceFindings from this study suggest that the serum NFL level is a highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.
| S-EPMC6440255 | biostudies-literature
Project description:ObjectiveRecently, an increasing number of studies have suggested using serum neurofilament light (NfL) chain to predict the neurologic outcome after cardiac arrest. However, the predictive ability of this approach remains inconclusive. Meta-analysis was performed on related studies to assess the ability of serum NfL to predict the neurologic outcome after cardiac arrest.Materials and methodsPubMed, ScienceDirect and Embase were systematically searched from the date of their inception until June 2022. Data were extracted to calculate the area under the receiver operating characteristic curve (AUC), the sensitivity, the specificity and the publication bias to evaluate the predictive power of serum NfL using Stata 14.0.ResultsNine studies were included in the present meta-analysis. Seven studies involving 1296 participants reported serum NfL 24 h post arrest for predicting the neurological outcome, and the AUC was 0.92 (77% sensitivity and 96% specificity). Seven studies involving 1020 participants reported serum NfL 48 h post arrest for predicting the neurological outcome, and the AUC was 0.94 (78% sensitivity and 98% specificity). Four studies involving 804 participants reported serum NfL 72 h post arrest for predicting the neurological outcome, and the AUC was 0.96 (90% sensitivity and 98% specificity). No significant publication bias was observed among the included studies.ConclusionThe present meta-analysis results support the potential use of serum NfL as an early biomarker of neurologic outcome, especially 72 h post arrest.
| S-EPMC10105388 | biostudies-literature
Project description:BackgroundThe European Resuscitation Council 2021 guidelines for haemodynamic monitoring and management during post-resuscitation care from cardiac arrest call for an individualised approach to therapeutic interventions. Combining the cardiac function and venous return curves with the inclusion of the mean systemic filling pressure enables a physiological illustration of intravascular volume, vasoconstriction and inotropy. An analogue mean systemic filling pressure (Pmsa) may be calculated once cardiac output, mean arterial and central venous pressure are known. The NEUROPROTECT trial compared targeting a mean arterial pressure of 65 mmHg (standard) versus an early goal directed haemodynamic optimisation targeting 85 mmHg (high) in ICU for 36 h after cardiac arrest. The trial data were used in this study to calculate post hoc Pmsa and its expanded variables to comprehensively describe venous return physiology during post-cardiac arrest management. A general estimating equation model was used to analyse continuous variables split by standard and high mean arterial pressure groups.ResultsData from 52 patients in each group were analysed. The driving pressure for venous return, and thus cardiac output, was higher in the high MAP group (p < 0.001) along with a numerically increased estimated stressed intravascular volume (mean difference 0.27 [- 0.014-0.55] L, p = 0.06). The heart efficiency was comparable (p = 0.43) in both the standard and high MAP target groups, suggesting that inotropy was similar despite increased arterial load in the high MAP group (p = 0.01). The efficiency of fluid boluses to increase cardiac output was increased in the higher MAP compared to standard MAP group (mean difference 0.26 [0.08-0.43] fraction units, p = 0.01).ConclusionsCalculation of the analogue mean systemic filling pressure and expanded variables using haemodynamic data from the NEUROPROTECT trial demonstrated an increased venous return, and thus cardiac output, as well as increased volume responsiveness associated with targeting a higher MAP. Further studies of the analogue mean systemic filling pressure and its derived variables are warranted to individualise post-resuscitation care and evaluate any clinical benefit associated with this monitoring approach.
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Project description:AimTo determine the ability of serum glial fibrillary acidic protein (GFAp) and tau protein to predict neurological outcome after out-of-hospital cardiac arrest (OHCA).MethodsWe measured plasma concentrations of GFAp and tau of patients included in the previously published COMACARE trial (NCT02698917) on intensive care unit admission and at 24, 48, and 72 h after OHCA, and compared them to neuron specific enolase (NSE). NSE concentrations were determined already during the original trial. We defined unfavourable outcome as a cerebral performance category (CPC) score of 3-5 six months after OHCA. We determined the prognostic accuracy of GFAp and tau using the receiver operating characteristic curve and area under the curve (AUROC).ResultsOverall, 39/112 (35%) patients had unfavourable outcomes. Over time, both markers were evidently higher in the unfavourable outcome group (p < 0.001). At 48 h, the median (interquartile range) GFAp concentration was 1514 (886-4995) in the unfavourable versus 238 (135-463) pg/ml in the favourable outcome group (p < 0.001). The corresponding tau concentrations were 99.6 (14.5-352) and 3.0 (2.2-4.8) pg/ml (p < 0.001). AUROCs at 48 and 72 h were 0.91 (95% confidence interval 0.85-0.97) and 0.91 (0.85-0.96) for GFAp and 0.93 (0.86-0.99) and 0.95 (0.89-1.00) for tau. Corresponding AUROCs for NSE were 0.86 (0.79-0.94) and 0.90 (0.82-0.97). The difference between the prognostic accuracies of GFAp or tau and NSE were not statistically significant.ConclusionsAt 48 and 72 h, serum both GFAp and tau demonstrated excellent accuracy in predicting outcomes after OHCA but were not superior to NSE.Clinical trial registrationNCT02698917 (https://www.clinicaltrials.gov/ct2/show/NCT02698917).
| S-EPMC8786666 | biostudies-literature
Project description:Background and objectivesTo investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity.MethodsA post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline. We investigated the association of pNfL levels with disability progression, cognitive decline, and brain atrophy and their sensitivity to indicate treatment response through clinical measures.ResultsWe analyzed pNfL in 4,185 samples from 1,452 patients with SPMS and 1,172 samples from 378 patients with PPMS. Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001). In both studies, higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale score, more Gd+ lesions, and higher T2 lesion load (all p < 0.05). Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]), earlier wheelchair dependence (SPMS [50%], 1.50 [0.96-2.34]; PPMS [197%], 2.97 [1.44-6.10]), cognitive decline (SPMS [41%], 1.41 [1.09-1.84]), and higher rates of brain atrophy (mean change at month 24: SPMS, -0.92; PPMS, -1.39). Baseline pNfL levels were associated with future disability progression and the degree of brain atrophy regardless of presence or absence of acute disease activity (gadolinium-enhancing lesions or recent occurrence of relapses before baseline). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression.DiscussionpNfL was associated with future clinical and radiologic disability progression features at the group level. pNfL was reduced by treatment and may be a meaningful outcome measure in PMS studies.Trial registration informationEXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).
| S-EPMC10263182 | biostudies-literature
Project description:BackgroundThe phase 3 TERIKIDS study demonstrated efficacy and manageable safety for teriflunomide versus placebo in children with relapsing multiple sclerosis (RMS).ObjectiveEvaluate plasma neurofilament light chain (pNfL) concentrations in TERIKIDS.MethodsPatients received placebo or teriflunomide (14 mg adult equivalent) for up to 96 weeks in the double-blind (DB) period. In the open-label extension (OLE), all patients received teriflunomide until up to 192 weeks after randomization. pNfL was measured using single-molecule array assay (Simoa® NF-light™).ResultsBaseline mean age was 14.5 years; 69.4% were female. Baseline geometric least square mean pNfL levels were similar for teriflunomide (n = 78) and placebo (n = 33) patients (19.83 vs 18.30 pg/mL). Over the combined DB and OLE periods, pNfL values were lower for teriflunomide versus placebo (analysis of variance p < 0.01; Week 192: 10.61 vs 17.32 pg/mL). Observed between-group pNfL differences were attenuated upon adjustment for gadolinium (Gd)-enhancing or new/enlarged T2 lesion counts at DB Week 24. Higher baseline pNfL levels were associated with shorter time since first MS symptom onset, higher baseline Gd-enhancing lesion counts and T2 lesion volume, and increased hazard of high magnetic resonance imaging activity or clinical relapse during the DB period.ConclusionTeriflunomide treatment was associated with significantly reduced pNfL levels in children with RMS.Clinicaltrials.gov identifierNCT02201108.
| S-EPMC9972233 | biostudies-literature
Project description:BackgroundTransthoracic echocardiographic (TTE) indices of myocardial function among survivors of out-of-hospital cardiac arrest (OHCA) have been related to neurological outcome; however, results are inconsistent. We hypothesized that changes in average peak systolic mitral annular velocity (s') from 24 h (h) to 72 h following start of targeted temperature management (TTM) predict six-month neurological outcome in comatose OHCA survivors.MethodsWe investigated the association between peak systolic velocity of the mitral plane (s') and six-month neurological outcome in a population of 99 patients from a randomised controlled trial comparing TTM at 33 ± 1 °C for 24 h (h) (n = 47) vs. 48 h (n = 52) following OHCA (TTH48-trial). TTE was conducted at 24 h, 48 h, and 72 h after reaching target temperature. The primary outcome was 180 days neurological outcome assessed by Cerebral Performance Category score (CPC180) and the primary TTE outcome measure was s'. Secondary outcome measures were left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), e', E/e' and tricuspid annular plane systolic excursion (TAPSE).ResultsAcross all three scan time points s' was not associated with neurological outcome (ORs: 24 h: 1.0 (95%CI: 0.7-1.4, p = 0.98), 48 h: 1.13 (95%CI: 0.9-1.4, p = 0.34), 72 h: 1.04 (95%CI: 0.8-1.4, p = 0.76)). LVEF, GLS, E/e', and TAPSE recorded on serial TTEs following OHCA were neither associated with nor did they predict CPC180. Estimated median e' at 48 h following TTM was 5.74 cm/s (95%CI: 5.27-6.22) in patients with good outcome (CPC180 1-2) vs. 4.95 cm/s (95%CI: 4.37-5.54) in patients with poor outcome (CPC180 3-5) (p = 0.04).Conclusionss' assessed on serial TTEs in comatose survivors of OHCA treated with TTM was not associated with CPC180. Our findings suggest that serial TTEs in the early post-resuscitation phase during TTM do not aid the prognostication of neurological outcome following OHCA.Trial registrationNCT02066753 . Registered 14 February 2014 - Retrospectively registered.
| S-EPMC7893899 | biostudies-literature
Project description:BackgroundImpaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury.MethodsA post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury.ResultsIn 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042).ConclusionImpaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .
| S-EPMC8477475 | biostudies-literature