Absolute serum neurofilament light chain levels and its early kinetics predict brain injury after out-of-hospital cardiac arrest

Severe hypoxic-ischemic brain injury (sHIBI) is the major cause of death in patients successfully resuscitated following out of hospital cardiac arrest (OHCA) [1]. However, most of these deaths are not directly caused by sHIBI but rather result from withdrawal of life support (WLS) following unfavorable neuroprognostication [2, 3]. The 2021 joint guidelines of the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine recommend neuroprognostication no earlier than 72 h after return of spontaneous circulation (ROSC) and in comatose patients with a motor response ≤ 3 of the Glasgow Coma Scale (abnormal flexion, extension, or nil) [4]. The use of sedatives and targeted temperature management (TTM) is among the reasons for this suggestion. Neuroprognostication following OHCA is paramount not only to guide treating physicians and families in deciding whether or not to continue life support, but also to avoid the overuse of limited intensive care resources, even more so in light of a global pandemic.

Neurofilament proteins are part of the neuronal cytoskeleton and are released into the CSF and subsequently in the peripheral blood upon neuroaxonal damage [5]. Technical developments have introduced highly sensitive single-molecule assays (SiMoA) for reliable, easily accessible measurements of neurofilament light chain levels in blood samples (NFL). NFL is currently emerging as a diagnostic blood-marker for neuronal injury in neurodegenerative, inflammatory, and ischemic diseases of the central nervous system (CNS) [5‐7]. Data on the value of NFL for prognostication following OHCA is evolving: in a biobanking study involving 29 participating sites, NFL levels in blood were shown to predict the outcome in 782 unconscious patients with OHCA of presumed cardiac origin, measured 24 to 72 h following hospital admission. NFL levels above 641.4 pg/ml at 24 h after cardiac arrest had a 99% specificity for poor outcome [8], confirming data of an earlier ELISA-based smaller cohort study [9]. These findings have independently been confirmed in recent studies: in a post-hoc analysis of another study involving 120 patients and assessment in blood taken at 48 h of admission, median NFL concentrations in plasma were found higher in patients with poor outcome compared to those with good outcome (2343 vs. 19 pg/ml), with the outcome assessed at month 6 of admission [10]. In a single-center study including 164 OHCA patients, NFL was measured already within 24 h of admission, and the median NFL values were higher in patients with poor outcome compared to those with good outcome (116 vs. 27 pg/mL) [11]. The three key studies mentioned allow the conclusion that NFL should be further evaluated for the purpose of neuroprognostication of OHCA patients in clinical routine.

Our study tested the value of NFL levels in blood samples of a monocentric cohort of OHCA patients, with a baseline sample taken within the first 3 h of admission, and then after 24 and 48 h. Thus, as the published studies lack an early baseline sampling, we aimed to test if an early increase (delta NFL) adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL and its early kinetics can discriminate cases with sHIBI from other causes of poor outcome after OHCA.

In this study, we could confirm that NFL is a highly specific marker for poor outcome (CPC3–5) following OHCA, superior to NSE currently used in clinical practice. The cut-point at 641.4 pg/ml in the largest study published and measured at 48 h of admission was associated with CPC 3–5 in all patients of this smaller independent cohort tested [8]. As a novel observation, an increase in NFL of > 494 pg/ml comparing values at baseline (within the first 3 h of admission) and after 48 h also predicted poor outcome in our cohort. Low NFL baseline values found early after OHCA in all individuals, and the consecutive increase in patients with unfavorable outcome strongly support the validity of NFL for prognostication and corroborates the conclusion that NFL should be considered as a standard laboratory measure in the evaluation of OHCA patients [8‐10]. Our finding is of importance for the design of independent larger prospective studies in which an early baseline sampling should be obtained.

As shown most clearly in Fig. 2C for the early delta NFL in patients with CPC3–5, the patients split into those with only marginal or no NFL increase, and a proportion of around 50% of patients with an increase in NFL far beyond 494 pg/ml, thereby separating two distinct populations: a population that could be classified as individuals with “poor neurological outcome likely” according to the prognostication strategy algorithm proposed by the European Resuscitation Council and the European Society of Intensive Care Medicine [4] with very high NFL values classified as sHIBI; and a population with comparably low NFL values considered as patients without sHIBI, and a poor outcome due to other causes of limited patient prognosis, such as severe multi-organ dysfunction syndrome not primarily involving the brain.

Both NSE and NFL are abundantly found in neurons and their release into the blood stream indicates neuronal damage. NSE is the most widely used and best investigated biomarker for neuroprognostication in cardiac arrest patients [17‐19]. However, release of NSE into the peripheral blood is not specific for neuronal damage. NSE has not only been found in neurons but also in neuronendocrine tumors, paraneuronal tissue and even red blood cells and platelets [20‐22]. Therefore, concurrent neuroendocrine tumors or massive hemolysis are among potential confounders for NSE levels, possibly explaining a lower specificity of NSE compared to NFL for neuroprognostication found in our study, and confirming the published literature. In contrast, NFL is part of neuronal cytoskeleton, only expressed in neurons and, therefore, is a highly specific marker of neuronal damage [5].

Futile medical care has many definitions [23] but typically depends on the probability of reaching goals of treatment [24]. sHIBI following OHCA is a typical scenario for medical futility. A European-wide survey revealed that most people would not like to be kept alive in case of a permanent vegetative or minimally conscious state [25]. Accordingly, Dragancea and colleagues demonstrated withdrawal of life support to be the most common cause of death in patients with OHCA that reach the ICU [2].

In times of resource-constrained healthcare systems, accurate and rapid prognostication of outcome in intensive care patients is warranted. In patients successfully resuscitated following OHCA, absolute NFL, and early changes of NFL measured in blood—in combination with standard prognostication criteria [2, 3]—has the potential to ease decision-making for medical personal and family, reduce economic impact and preserve urgently needed ICU capacities, in particular in the times of a global pandemic.

Our study has several limitations. First, it is a retrospective monocentric cohort study, with limitations inherent to study design. This resulted, e.g., in a predominance of the male gender, and a retrospective classification of patients as sHIBI based on chart review according to published algorithms. Despite the independent evaluation of clinical parameters by two of the investigators, not all further investigations required were performed in all individuals to predict outcome following OHCA, reducing the likelihood to classify individuals as sHIBI. This may have resulted in an overestimation of the predictive value of NFL for sHIBI in our study, making prospective validation mandatory. Second, absolute values of NFL measured by SiMoA published in recent years are not directly comparable due to a lack of standardization of NFL assays between different laboratories. Therefore, although our study resulted in cut-off values at 48 h to predict outcome following OHCA comparable to the largest published applying a similar technique [8], the assay validation steps were not identical, and additional external validation is needed before the use of absolute cut-off values for prognostication in clinical practice. The same applies to the establishment of the measurement of early NFL dynamics for prognostication.

Our study investigating NFL levels in patients with non-traumatic OHCA corroborates previous studies showing that absolute NFL values should be considered as a standard laboratory measure in prognostication of OHCA patients. As a novel finding, we also studied NFL in blood samples early after admission allowing to assess the early NFL dynamics. An early increase in NFL also predicted poor outcome with high specificity, and may early help to identifying individuals with severe brain hypoxia. Thus, NFL measurements in blood should become broadly available to be used in the clinical routine on standard laboratory instruments to enable prospective validation, and its use for prognostication in critical care medicine.