OBJECTIVES: To perform a detailed examination of sodium levels, hyponatremia and sodium fluctuations, and their association with delayed cerebral ischemia (DCI) and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). DESIGN: An observational cohort study from a prospective SAH Registry. SETTING: Tertiary referral center focused on SAH treatment in the Amsterdam metropolitan area. PATIENTS: A total of 964 adult patients with confirmed aSAH were included between 2011 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 277 (29%) developed DCI. Hyponatremia occurred significantly more often in DCI patients compared with no-DCI patients (77% vs. 48%). Sodium levels, hyponatremia, hypernatremia, and sodium fluctuations did not predict DCI. However, higher sodium levels were significantly associated with poor outcome in DCI patients (DCI onset –7, DCI +0, +1, +2, +4, +5, +8, +9 d), and in no-DCI patients (postbleed day 6–10 and 12–14). Also, hypernatremia and greater sodium fluctuations were significantly associated with poor outcome in both DCI and no-DCI patients. CONCLUSIONS: Sodium levels, hyponatremia, and sodium fluctuations were not associated with the occurrence of DCI. However, higher sodium levels, hypernatremia, and greater sodium fluctuations were associated with poor outcome after aSAH irrespective of the presence of DCI. Therefore, sodium levels, even with mild changes in levels, warrant close attention.

Delayed cerebral ischemia (DCI) substantially contributes to disability and death in subarachnoid hemorrhage (SAH) patients; however, its pathophysiology is incompletely understood and diagnostic and therapeutic strategies are lacking. Biomarkers may help to elucidate the pathophysiology, optimize early diagnosis, or provide treatment targets. We systematically searched PubMed and Embase on October 13, 2021, for studies that evaluated at least one laboratory biomarker in patients with DCI, using the most up-to-date definition of DCI as proposed by a panel of experts in 2010. Quality of studies was assessed using the Newcastle-Ottawa Scale or Cochrane Collaboration’s risk of bias assessment tool. Biomarkers of clinical and radiological DCI were analyzed separately. Results were meta-analyzed if possible, otherwise narratively reviewed. Biomarkers were classified as significant, inconclusive, or nonsignificant. We defined validated biomarkers as those with significant results in meta-analyses, or in at least two studies using similar methodologies within the same time interval after SAH. The search yielded 209 articles with 724 different biomarkers; 166 studies evaluated 646 biomarkers of clinical DCI, of which 141 were significant and 7 were validated biomarkers (haptoglobulin 2-1 and 2-2, ADAMTS13, vWF, NLR, P-selectin, F2-isoprostane); 78 studies evaluated 165 biomarkers of radiological DCI, of which 63 were significant and 1 was a validated biomarker (LPR). Hence, this review provides a selection of seven biomarkers of clinical DCI and one biomarker of radiological DCI as most promising biomarkers of DCI. Future research should focus on determining the exact predictive, diagnostic, and therapeutic potentials of these biomarkers.

Neurofilament light chain (NfL), a biomarker reflecting neuro-axonal damage, may be useful in improving clinical outcome prediction after aSAH. We explore the robust and additional value of NfL to neurological and radiological grading scales in predicting poor outcome after aSAH. In this prospective cohort study conducted in a single tertiary center, blood samples were collected of aSAH patients within 24 hours after ictus and before endovascular/surgical intervention. The primary endpoint was poor outcome at six months' follow-up. Receiver operating curves (ROC), area under the curve (AUC, 95% CI) and model-fit (Nagelkerke R²) were calculated for NfL, neurological grading scale (WFNS), modified Fisher, age and sex. A combined ROC and AUC were calculated for variables with an AUC≥0.70. A total of 66 (42%) had poor outcome. The AUC of NfL for poor outcome was 0.70 (0.62-0.78). Combining NfL and WFNS resulted in a slightly higher model-fit and not-significantly higher AUC for predicting poor outcome (R² 0.51; AUC 0.86, 0.80-0.92) compared to WFNS alone. When patients were stratified according to hemorrhage severity, median NfL [IQR] levels were significantly higher in poor grade (14 [7-32] pg/ml) than good grade patients (7 [5-14] pg/ml). Within poor grade patients, median NfL [IQR] levels were significantly higher in non-survivors (19 [11-36] pg/ml) than survivors (7 [6-13] pg/ml). In the entire aSAH cohort, plasma NfL has an acceptable predictive performance but does not improve clinical outcome prediction. However, NfL may have potential value in subgroups based on hemorrhage severity.