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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter / Tate, Jillian R.

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An improved laboratory protocol to assess subarachnoid haemorrhage in patients with negative cranial CT scan

Joke J. Apperloo1 / Fedde van der Graaf2 / Paul L.I. Dellemijn3 / Huib L. Vader4





Corresponding author: Joke J. Apperloo, PhD, Laboratory of Clinical Chemistry, Máxima Medical Centre, De Run 4600, 5500 MB Veldhoven, The Netherlands Phone: +31-40-8888900, Fax: +31-40-8888909,

Citation Information: Clinical Chemical Laboratory Medicine. Volume 44, Issue 8, Pages 938–948, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2006.171, July 2006

Publication History

November 3, 2005
May 3, 2006
Published Online:


Background: The laboratory analysis of cerebrospinal fluid (CSF) plays a key role in considering subarachnoid haemorrhage (SAH) in patients with clinical suspicion, but negative CT scan. Although the determination of the CSF bilirubin concentration generally provides high sensitivity, it was recently shown that specificity and positive predictive value are unacceptably low, limiting its use as a diagnostic tool.

Methods: We intended to design and evaluate an improved laboratory protocol, which fulfills the requirement of better specificity without losing sensitivity. We present a procedure in which a “bili-excess” concentration is determined, which is the surplus CSF bilirubin measured after subtraction of an estimated upper limit for the individual patient. The latter is calculated from [bilirubin]serum, [albumin]serum and [albumin]CSF, taking into account the propagation of analytical errors in the individual analyses. We investigated the applicability of direct absorption vs. derivative spectroscopy, thereby addressing the influence of various calibration methods. We evaluated our procedure in 92 CSF samples drawn from patients with (n=37) and without (n=55) clinical suspicion of SAH.

Results: In our study population, we show that specificity increases from 0.83 (95% CI, 0.74–0.91) to 1.00 (95% CI, 0.96–1.00) using the bili-excess concept, with an established upper limit for bili-excess of 0.11 μmol/L instead of the recommended use of an “uncorrected” CSF bilirubin upper limit of 0.20 μmol/L. Sensitivity in both cases is 1.00 (95% CI, 0.66–1.00). We demonstrate the merit of allowing for analytical imprecision in the bili-excess concept.

Conclusions: We provide a quantitative procedure to explore the likelihood of (CT-negative) SAH independent of the absolute CSF bilirubin concentration by considering the “bili-excess” concentration per individual, using derivative spectroscopy to determine CSF bilirubin. This procedure led to an increase in specificity to 1.00 (95% CI, 0.96–1.00) in our study population.

Clin Chem Lab Med 2006;44:938–48.

Keywords: bili-excess; bilirubin; blood pigments; cerebrospinal fluid; subarachnoid haemorrhage

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