Beyond blood-brain barrier disruption and molecular weight: compartmental kinetics of S100B and NSE for neurological prognostication after cardiac arrest

Critical Care volume 29, Article number: 342, Published: 04 August 2025

 Background

The prognostic value of serum biomarkers after out-of-hospital cardiac arrest (OHCA) depends on timing, but the physiological basis remains unclear. We investigated whether blood–brain barrier (BBB) integrity and biomarker-specific properties explain the time-dependent differences in prognostic performance.

Methods

This retrospective study included comatose adult OHCA survivors who underwent paired serum and cerebrospinal fluid (CSF) measurements of neuron-specific enolase (NSE; 47 kDa) and S100 calcium-binding protein B (S100B; 21 kDa) at 0 (H0), 24 (H24), 48 (H48), and 72 (H72) h after return of spontaneous circulation. BBB disruption was assessed using the CSF/serum albumin quotient (Q_A). Prognostic performance was assessed using AUC analysis for 6-month poor neurological outcome (Cerebral Performance Category 3–5).

Results

Among 111 patients (59% poor outcome), 646 serum and 620 CSF samples were analyzed. BBB disruption was more severe in the poor outcome group at all timepoints (all P < 0.001), peaking at H24 (Q_A 0.0282 [IQR 0.0150–0.120]) and remaining elevated at H72 (0.0228 [IQR 0.0147–0.0598]). In the poor outcome group, serum S100B levels peaked at H0 (0.80 ng/mL [IQR 0.39–2.81]) and declined despite a persistent elevation in CSF levels at or above the upper detection limit (≥ 30 ng/mL). Conversely, NSE levels progressively increased in both compartments, with serum and CSF levels increasing in parallel over time. Serum NSE concentrations showed a time-dependent improvement in prognostic accuracy, peaking at H72 (AUC 0.88), whereas S100B concentrations maintained stable performance across all timepoints (AUCs 0.79–0.85, all P > 0.4). Notably, the prognostic performance of S100B remained relatively consistent regardless of BBB disruption severity, whereas NSE showed progressively improved predictive accuracy with increased BBB disruption. Across all timepoints, CSF biomarkers—particularly S100B and NSE—showed consistently higher AUCs than serum, suggesting superior prognostic utility.

Conclusions

Serum NSE levels closely reflect the degree of BBB disruption and CSF levels, while S100B exhibits a transient early-phase profile, with decreased serum detectability over time, even in the presence of sustained CSF elevation or severe BBB disruption. These findings highlight the importance of interpreting biomarker kinetics across compartments and timepoints rather than relying on molecular weight or BBB status alone.

 

Proenkephalin as a biomarker correlates with acute kidney injury: a systematic review with meta-analysis and trial sequential analysis

 

by Li-Chun Lin, Min-Hsiang Chuan, Jung-Hua Liu, Hung-Wei Liao, Leong L. Ng, Martin Magnusson, Amra Jujic, Heng-Chih Pan, Vin-Cent Wu and Lui G. Forni 

 

Critical Care volume 27, Article number: 481 (2023) Published: 07 December 2023

 

Background

Proenkephalin A 119-159 (PENK) is freely filtered in the glomerulus with plasma levels correlating with glomerular filtration rate. Therefore, PENK has been proposed as an early indicator of acute kidney injury (AKI) although its performance is dependent on the clinical setting. This meta-analysis aimed to investigate the correlation between PENK levels and the development of AKI.

Methods

We conducted a comprehensive search on the PubMed, Embase, Cochrane databases, the website ClinicalTrials.gov and Cnki.net until June 26, 2023. Summary receiver operating characteristic (SROC) curves were used to amalgamate the overall test performance. Diagnostic odds ratio (DOR) was employed to compare the diagnostic accuracy of PENK with other biomarkers. Quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria.

Results

We incorporated 11 observational studies with 3969 patients with an incidence of AKI of 23.4% (929 out of 3969 patients) with the best optimal cutoff value of PENK for early detection of AKI being 57.3 pmol/L. The overall sensitivity and specificity of PENK in identifying AKI were 0.69 (95% CI 0.62–0.75) and 0.76 (95% CI 0.68–0.82), respectively. The combined positive likelihood ratio (LR) stood at 2.83 (95% CI 2.06–3.88), and the negative LR was 0.41 (95% CI 0.33–0.52). The SROC curve showcased pooled diagnostic accuracy of 0.77 (95% CI 0.73–0.81). Interestingly, patients with a history of hypertension or heart failure demonstrated a lower specificity of PENK in correlating the development of AKI.

Conclusion

Our results indicate that PENK possesses significant potential as a biomarker for the early detection of the development of AKI, using a cutoff point of 57.3 pmol/L for PENK.

 

Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis

by Huang, Yu-Hsuan; Chen, Ching-Jung; Shao, Shih-Chieh; Li, Chih‑Huang; Hsiao, Chien-Han; Niu, Kuang-Yu; Yen, Chieh-Ching 

Critical Care Medicine ():10.1097/CCM.0000000000005820, March 06, 2023.

Objectives: 

We performed a systemic review and meta‐analysis to evaluate the diagnostic accuracy of monocyte distribution width (MDW) and to compare with procalcitonin and C‐reactive protein (CRP), in adult patients with sepsis.

Data Sources: 

A systematic literature search was performed in PubMed, Embase, and the Cochrane Library to identify all relevant diagnostic accuracy studies published before October 1, 2022.

Study Selection: 

Original articles reporting the diagnostic accuracy of MDW for sepsis detection with the Sepsis-2 or Sepsis-3 criteria were included.

Data Extraction: 

Study data were abstracted by two independent reviewers using a standardized data extraction form.

Data Synthesis: 

Eighteen studies were included in the meta‐analysis. The pooled sensitivity and specificity of MDW were 84% (95% CI [79–88%]) and 68% (95% CI [60–75%]). The estimated diagnostic odds ratio and the area under the summary receiver operating characteristic curve (SROC) were 11.11 (95% CI [7.36–16.77]) and 0.85 (95% CI [0.81–0.89]). Significant heterogeneity was observed among the included studies. Eight studies compared the diagnostic accuracies of MDW and procalcitonin, and five studies compared the diagnostic accuracies of MDW and CRP. For MDW versus procalcitonin, the area under the SROC was similar (0.88, CI = 0.84–0.93 vs 0.82, CI = 0.76–0.88). For MDW versus CRP, the area under the SROC was similar (0.88, CI = 0.83–0.93 vs 0.86, CI = 0.78–0.95).

Conclusions: 

The results of the meta-analysis indicate that MDW is a reliable diagnostic biomarker for sepsis as procalcitonin and CRP. Further studies investigating the combination of MDW and other biomarkers are advisable to increase the accuracy in sepsis detection.

 The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis

 

by Vanessa Catenacci, Fatima Sheikh, Kush Patel and Alison E. Fox-Robichaud 

 

Critical Care volume 26, Article number: 21 (2022) 

 

Background

Sepsis, the dysregulated host response to infection, triggers abnormal pro-coagulant and pro-inflammatory host responses. Limitations in early disease intervention highlight the need for effective diagnostic and prognostic biomarkers. Protein C’s role as an anticoagulant and anti-inflammatory molecule makes it an appealing target for sepsis biomarker studies. This meta-analysis aims to assess the diagnostic and prognostic value of protein C (PC) as a biomarker for adult sepsis.

Methods

We searched MEDLINE, PubMed, EMBASE, CINAHL and Cochrane Library from database inception to September 12, 2021. We included prospective observational studies of (1) adult patients (> 17) with sepsis or suspicion of sepsis that; (2) measured PC levels with 24 h of study admission with; and (3) the goal of examining PC as a diagnostic or prognostic biomarker. Two authors screened articles and conducted risk of bias (RoB) assessment, using the Quality in Prognosis Studies (QUIPS) and the Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools. If sufficient data were available, meta-analysis was conducted to estimate the standardized mean difference (SMD) between patient populations.

Results

Twelve studies were included, and 8 were synthesized for meta-analysis. Pooled analysis demonstrated moderate certainty of evidence that PC levels were less reduced in sepsis survivors compared to non-survivors (6 studies, 741 patients, SMD = 0.52, 95% CI 0.24–0.81, p = 0.0003, I2 = 55%), and low certainty of evidence that PC levels were less reduced in septic patients without disseminated intravascular coagulation (DIC) compared to those with DIC (3 studies, 644 patients, SMD = 0.97, 95% CI 0.62–1.32, p < 0.00001, I2 = 67%). PC could not be evaluated as a diagnostic tool due to heterogeneous control populations between studies.

Conclusion and relevance

Our review demonstrates that PC levels were significantly higher in sepsis survivors compared to non-survivors and patients with sepsis but not disseminated intravascular coagulation (DIC). Our evaluation is limited by high RoB in included studies and poor reporting of the sensitivity and specificity of PC as a sepsis biomarker. Future studies are needed to determine the sensitivity and specificity of PC to identify its clinical significance as a biomarker for early sepsis recognition