Serum Test Marker for Brain Death
There is no established serum test marker that can definitively diagnose brain death, as brain death remains a clinical diagnosis confirmed by neurological examination and apnea testing, with ancillary tests like EEG or cerebral blood flow studies when needed. However, serum S100B protein shows promise as a supportive biomarker, with concentrations >1.81 μg/L demonstrating high accuracy in predicting brain death 1.
S100B as a Supportive Marker
Serum S100B protein concentrations are extremely elevated in brain-dead organ donors and may support the clinical diagnosis of brain death, particularly when reflex movements complicate the determination. 1
Evidence for S100B in Brain Death
Brain-dead organ donors demonstrate median S100B values of 5.04 μg/L (IQR: 1.775-6.765), which are significantly higher than patients with permanent neurological deficits without brain death (0.897 μg/L; IQR: 0.324-1.880, P < 0.001) 1
A cutoff value >1.81 μg/L predicts brain death with the highest accuracy (AUROC = 0.83; 95% CI 0.68-0.93; P < 0.001) 1
Sustained elevations of S100B over 24 hours, particularly when combined with other biomarkers like GFAP and NSE, can more reliably predict the extent of brain injury and clinical outcomes 2
Mechanism and Biology
S100B is an astrocyte-specific CNS protein that is released following neuronal injury and crosses the disrupted blood-brain barrier into peripheral circulation 3
The protein has a short half-life of approximately 97 minutes, making timing of measurement crucial 3
Peak S100B values demonstrate the highest correlation to injury severity and outcome parameters 4
Critical Limitations and Caveats
S100B should never be used as the sole criterion for determining brain death due to significant specificity limitations. 2
Major Pitfalls to Avoid
Extracerebral sources: S100B is found in adipocytes, chondrocytes, skin, and cartilage, leading to false elevations in patients with significant extracranial injuries 3, 5, 6
Hemolysis sensitivity: S100B measurements are highly sensitive to hemolysis, which can produce false-positive results 7
Laboratory variability: Standards for S100B measurement vary between centers, making comparison of absolute values difficult 7
Timing dependency: S100B levels show a highly time-dependent temporal course, with measurements needing to occur within specific windows after injury 4
Alternative Biomarkers
Neuron-Specific Enolase (NSE)
NSE is more specific for CNS injury with minimal extracranial sources compared to S100B 2
NSE levels in CSF are proportional to TBI severity and associated with increased mortality in moderate or severe TBI 7
However, NSE should not be used alone to predict neurological outcomes due to high false-positive rates 7
CSF/Serum Albumin Ratio
An elevated CSF/serum albumin ratio indicates blood-brain barrier disruption and is the standard biomarker for BBB integrity 3, 8
A ratio >20 strongly indicates BBB disruption, though this is more applicable to severe TBI than brain death determination 8
Clinical Application Algorithm
When evaluating potential brain death:
Primary diagnosis: Establish brain death through standard clinical criteria (absent brainstem reflexes, apnea test, known irreversible cause) - this remains the gold standard
Consider S100B measurement when:
Interpret S100B results cautiously:
Combine with other biomarkers if available:
The critical caveat is that serum biomarkers can only support, never replace, the clinical diagnosis of brain death established through neurological examination and standard confirmatory testing.