CSF bilirubin-spectrophotometry or direct measurement?
CSF bilirubin-spectrophotometry or direct measurement?
Department of Clinical Biochemistry, North Bristol NHS Trust (Frenchay Hospital), Bristol BS16 1LE, UK
Ann Clin Biochem 2007; 44: 99–100.
It is of vital importance not tomiss the diagnosis of subarachnoid haemorrhage (SAH). Where it is missed, and this is most likely to be in those who are neurologically intact at presentation, the consequences of rebleeding and vasospasm can be very serious and leave the patient with signi¢cantly more neurological impairment than would have been the case had the original bleed been diagnosed and appropriately treated.1 The reasons formisdiagnosis are ¢rstly, failure to appreciate the spectrum of clinical presentation; secondly, failure to understand the limitations of computed tomography (CT); and thirdly, failure to performand correctly interpret the results of lumbar puncture.1
Once the diagnosis has been entertained, the appropriate investigation is CTof the headwithout contrast for the presence of blood.2 This will be positive in up to 98% of patients scanned within 12 h of a bleed, but positivity drops o¡ with time such that it may be only 50% sensitive at one week after a bleed.3,4 While new generation scanners may return an even higher sensitivity than quoted,5 at present it is still well accepted that a negative scan does not exclude an SAH.1 A follow-on test is then necessary to delineate those few patients in whom cerebral angiography is indicated.
There has been much debate over the years as to which follow-on test is most appropriate and current recommendations, supported by sound evidence, are that cerebrospinal £uid (CSF) taken by lumbar puncture should be examined spectrophotometrically for the presence of bilirubin.6,7 Nevertheless, worldwide, particularly across theAtlantic, the majority of investigators use visual inspection to con¢rm the presence of bilirubin, partly because of the claim that spectrophotometry needs dedicated equipment and skilled analysts, and, moreover, may be di⁄cult to interpret.8 While there is evidence from the UK National Quality Assessment Scheme for CSF Biochemistry and Haem Pigments that the necessary analytical and interpretative skills are present in the UK,9 an analysis that could be ‘simply’ performed on current automated platforms would be a distinct advantage, especially if this were available on a 24 h basis.
Thus, the article by Chao and colleagues in this issue (p. 140) is timely and of great interest.10 Building on previous work in which a standard serum bilirubin method was adapted for use with CSF,11 the authors have prospectively investigated the sensitivity and speci¢city of this method compared with spectrophotometry, with additional support being provided by outcome data.
Their results indicate that the method has appropriate sensitivity to detect samples that would be positive by spectrophotometry, without any signi¢cant compromise in speci¢city. It could thus act as an initial screening method to eliminate those samples that would subsequently prove to be negative spectrophotometrically, thereby allowing the majority of samples to be screened out by a procedure potentially available on a 24 h basis. The authors propose that samples positive by the modi¢ed serumbilirubinmethod then be subject to spectrophotometry for con¢rmation.
While this is an extremely attractive proposition, there remain a number of important caveats that must be made before such a procedure is adopted widely. As the authors observe, it is imperative that each laboratory meticulously validates the performance of any modi¢ed serum assay that they propose to use including the cut-o¡ that would decide whether a sample is deemed negative or should be subject to spectrophotometry. In this respect the authors note that the cut-o¡ of 359 nmol/L, which they previously used and have essentially con¢rmed in the present study, does not correspond to the net bilirubin absorbance (NBA) of 0.007 AU at 476 nm currently recommended, but equates instead to 0.015 AU; and that a plot of bilirubin against NBA had a positive intercept of 284 nmol/L. A satisfactory explanation for these discrepancies would be welcome. Moreover, any problems of the expertise required by spectrophotometry would be swapped for an alternative set of challenges, those of maintaining consistent quality in a user-de¢ned assay employing bilirubin calibrants and controls at one-tenth to onehundredth of the concentrations currently used for serum assays. Ultimately, the quality of such assays would require to be monitored in an External Quality Assessment Scheme. Finally, if spectrophotometry is to be employed only for those few samples positive by the screening test, there will inevitably have to be a concentration of spectrophotometry in a few centres of excellence. This may result in an unacceptable analytical delay to precisely those samples where a decision on the necessity of patient referral to specialist neurosurgery centres for further investigations needs to be reached quickly.
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10 Chao C-Y, Florkowski CM, Fink JN, Southby SJ, George PM. Prospective validation of cerebrospinal fluid bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2007; 44: 140–4
11 Ungerer JPJ, Southby SJ, Florkowski CM, George PM. Automated measurement of cerebrospinal fluid bilirubin in suspected subarachnoid haemorrhage. Clin Chem 2004; 50: 1854–6.
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