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Xanthochromia: a survey of laboratory methodology and its clinical implications.

Most cases of subarachnoid hemorrhage (SAH) are established by computed tomographic (CT) scanning of the brain. However, when the CT result is negative for SAH, equivocal, or technically inadequate, most physicians recommend that a lumbar puncture (LP) be performed. (1-4) In these latter cases, the physician analyzes the cerebrospinal fluid (CSF) for both red blood cells and xanthochromia. Xanthochromia (yellow color) is caused by breakdown of hemoglobin in the CSF that follows a hemorrhage, with resultant oxyhemoglobin, methemoglobin, and bilirubin formation. Oxyhemoglobin can form either in vitro or in vivo, but bilirubin is an enzyme-dependent in vivo process that requires time. (1,5) Xanthochromia is usually used to refer to all of these pigments. Although xanthochromia can occur with other entities, SAH is the most significant. (5)

To properly interpret the results of any diagnostic test, whether from the clinical laboratory or the radiology department, clinicians ought to know what test is being used and what the performance characteristics of that test are.

Many authorities on the diagnosis of SAH recommend a delay in performing the LP of at least 12 hours after the onset of symptoms to ensure that sufficient time has elapsed for measurable bilirubin in the CSF to appear. (2,6-7) This recommendation is based on one study, which demonstrated that between 12 hours and 2 weeks following the ictus, all patients with CT-proven SAH had xanthochromia as measured by spectrophotometry. (8) However, many, if not most, hospitals perform the measurement by simple visual inspection, which is not as sensitive. (9) Our hypothesis was that most hospital clinical laboratories in the United States did not use spectrophotometry to measure xanthochromia. If our hypothesis were true, then the foundation underlying the recommendation to delay LP by 12 hours becomes significantly eroded. This would have important patient care implications.

METHODS

We mailed a structured questionnaire to clinical laboratory directors at 3500 hospitals, most of which were in the United States. The questionnaire was sent as part of a routine proficiency testing program performed by the College of American Pathologists' Chemistry Resource Committee. That organization sends specimens 3 times per year for testing of laboratories. On the organization's routine M-A 2001 Cerebrospinal Fluid Chemistry Survey Test Result form, which was mailed on January 22, 2001, we added 7 supplemental questions (Table). Laboratory directors were instructed as follows: "The Chemistry Resource Committee is conducting a short survey to assess the state of the art for xanthochromia testing. Information on the method used in your laboratory to measure xanthochromia would be appreciated. Please provide answers to the supplemental questions."

Defined response options were given to assist in computerized data retrieval and analysis. Response to the proficiency test in general and to these supplemental questions in particular was voluntary. Results were received back within 1 month, and data analysis began on February 19, 2001. The questions are listed in the Table.

RESULTS

Of the 3500 questionnaires distributed, 2551 laboratories (72.9%) responded to the supplemental questions on xanthochromia (Table). Of those 2551 respondents, 1944 (76.2%) said that they evaluated CSF for xanthochromia. The remainder of the results relate to this latter group who performed the test at all. Regarding question 2, 1798 (91.8%) of 1959 laboratories routinely reported on xanthochromia; the others did so only when requested. Of the 1952 laboratories that answered question 3, 1947 (99.7%) responded that they used visual inspection.

Logically, because 1944 directors reported that they evaluated CSF for xanthochromia, 1944 or fewer should have responded to questions 2 and 3. However, there were more responses to questions 2 (1959) and 3 (1952) than the 1944 affirmative responses to question 1 (Table). Of a denominator of nearly 2000 total responses, this discrepancy was quite small.

Of the 8 laboratories using spectrophotometry, all but 1 used a single wavelength method.

Of the laboratories that responded to the question on turnaround time, 1378 (96.7%) of the 1425 said that they reported results in 2 hours or less. Because of the design of the questionnaire, there is no way to assess the availability or the turnaround time of the 8 laboratories that used spectrophotometry.

COMMENT

The results of our survey demonstrate unequivocally that most hospital clinical laboratories in the United States use visual inspection as the method for xanthochromia determination. In fact, of the respondents, 99.7% reported determining xanthochromia by visual inspection and not by spectrophotometry. Our survey was voluntary, and we had a response rate of 72.9%. If there were bias introduced, we speculate that laboratories sophisticated enough to use spectrophotometry would have been more likely to respond to the survey. However, even in the statistically remote possibility that all of the nonresponding laboratories used spectrophotometry, our findings would still indicate that nearly three quarters of laboratories used visual inspection.

As well, after we initiated our study, we found another report that was concordant with our findings. Judge (10) performed a telephone survey and found that of 805 hospital laboratory directors contacted, only 8 (1%) used spectrophotometry. We therefore feel confident in our conclusion that very few hospitals in the United States use spectrophotometry to determine xanthochromia. Another much smaller sample in Scotland reported that 15 of 15 hospitals used visual inspection, suggesting that the same situation may be true in parts of Europe as well. (11) That the method of visual inspection is used far more frequently than spectrophotometry is clearly statistically significant. But is it clinically significant?

Approximately 30 000 patients are diagnosed annually as having aneurysmal SAH in the United States. (1) In 2001, physicians diagnose the majority of such cases by CT scanning; patients with nondiagnostic CT scans then undergo LP. Because most patients being evaluated for acute severe headache and negative CT scans do not have SAH, a large number of patients without SAH undergo LP. (12,13) In this cohort of patients, the CSF is analyzed for various cellular and noncellular components. Unfortunately, there is no strict threshold number of erythrocytes in the CSF, below which a ruptured cerebral aneurysm is excluded. (1,4) As well, between 10% and 20% of all LPs are traumatic, meaning that blood was introduced into the CSF from needle trauma. (14,15) To complicate matters further, there is no generally accepted threshold number for what constitutes a traumatic tap.

To distinguish traumatic LP from true SAH, the clinician looks not only for red blood cells, but the yellowish discoloration that results from hemoglobin catabolism in the CSF or xanthochromia. Many believe that it is xanthochromia, not red blood cells, that forms the best diagnostic criterion for SAH. (8) In looking for xanthochromia, clinicians must consider the clinical context, method of measurement, and timing of onset of symptoms.

Xanthochromia from bilirubin requires time to develop. Some investigators have suggested that in patients being evaluated for SAH by LP, the attending physician should wait at least 12 hours from the onset of symptoms to allow sufficient time for bilirubin to form. The basis for this policy is the study by Vermeulen et al (8) in which 100% of 111 patients who underwent at least one LP performed between 12 hours and 2 weeks after onset of symptoms had xanthochromia. These investigators used spectrophotometry to measure xanthochromia in a retrospective review of patients.

All of their study patients had positive CT scans; in fact, this was an inclusion criterion for entry, thus introducing the possibility of a mild spectrum difference. By definition, patients undergoing LP in the evaluation of SAH have negative CT scans, which suggests they have had smaller bleeds, which might produce smaller amounts of bilirubin. (3) As well, because none of the patients in the study by Vermeulen et al had LPs performed before 12 hours, the study was not designed to evaluate any hypothesis other than performance at 12 hours. We do not know what percentage of those patients who presented early would have had xanthochromia had they undergone LP before 12 hours.

Can we extrapolate this policy to those patients being evaluated for SAH whose CT scans are negative and when the xanthochromia is being measured by visual inspection? Our survey does not answer this question. However, it is certainly possible that the time required for sufficient bilirubin to be detected visually is longer in this group (with negative CT scans). Because there are other reasons to not wait, such as the risk of ultra-early rebleeding, (16) logistical issues related to keeping patients for prolonged emergency department stays and the possibility of missing another serious diagnosis, we do not recommend delayed LP.

In addition, it is important to remember that essentially 100% of these patients who present early will have grossly bloody CSF, usually with very high numbers of erythrocytes that do not substantially diminish between the first and last samples collected. (17) There are other methods to distinguish traumatic tap from true hemorrhage. When used together, and in clinical context, we believe that the correct diagnosis can be made in most of these patients. (5) Furthermore, even xanthochromia as assessed visually is frequently present before 12 hours after onset of headache. In the pre-CT era, Walton (17) reported a series, probably the largest series ever, of 286 patients with SAH whose CSF was examined. Of the patients presenting between 0 and 12 hours, all had bloody CSF and almost half (43 of 89) had visually apparent xanthochromia. If only patients presenting between 6 and 12 hours are considered, a full two thirds (26 of 40) had xanthochromia. This early discoloration could be from oxyhemoglobin. However, if the CSF is rapidly centrifuged and examined, this oxyhemoglobin is almost certainly produced in vivo and, thus, a significant finding.

Clinicians need to understand the limitations and performance characteristics of any diagnostic tests that they use. Pathologists (and radiologists) need to understand what is the particular clinical question that is being asked. This requires clear communication between the 2 groups. Just as physicians evaluating patients for SAH must understand the decay in sensitivity of CT scanning with time, they must also know what method of xanthochromia detection their laboratory is using.

We conclude that most US hospital clinical laboratories use the visual inspection method for determining xanthochromia. We also believe that front-line physicians should not delay LP by 12 hours from onset of the patient's symptoms when attempting to diagnose SAH in those hospitals. In LPs done in the first 12 hours, clinicians should pay meticulous attention to technique, understand that all patients who present early with SAH will have bloody CSF, and use all the methods possible to distinguish between traumatic LP and a true SAH.
Xanthochromia Survey *

1. Does your laboratory evaluate
 cerebrospinal fluid for
 xanthochromia?

 Yes 1944 76.2%
 No 607 23.8%

 (if yes, please complete
 the remaining questions)

2. How often do you report
 on xanthochromia?

 Routinely 1798 91.8%
 Only when specified 161 8.2%

3. How do you report the results?

 Using visual inspection 1947 99.7%
 Using spectrophotometry 5 0.3%

4. If you report the results
 using spectrophotometry,
 which method do you use?

 A single wavelength 7 87.5%
 Scanning wavelengths 0 0%
 Multiple wavelengths 1 12.5%

5. The spectrophotometer used is
 (refer to master list)

 Hitachi (any model) 2 40%
 Coleman P.E. 2 40%
 Other 1 20%

6. Do you offer this test 24
 hours a day, 7 days a week?

 Yes 1525 97.3%
 No 43 2.7%

7. The typical turnaround time is:

 0-30 minutes 286 20%
 31-60 minutes 960 67.4%
 61-180 minutes 140 9.8%
 >180 minutes 39 2.7%

* The total number of affirmative responses for question 1 is 1944.
This should be the same as the total number of responses for question
2 (1959) and question 3 (1952). This likely resulted from confusion on
the part of some respondents. However, the number of discrepancies
is quite small relative to the denominator.

Participant data used with permission from the College of American
Pathologists.


Accepted for publication November 8, 2001.

References

(1.) Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage [see comments]. N Engl J Med. 2000;342:29-36.

(2.) Vermeulen M, van Gijn J. The diagnosis of subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 1990;53:365-72.

(3.) van der Wee N, Rinkel GJ, Hasan D, van Gijn J. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after a negative scan? J Neurol Neurosurg Psychiatry. 1995;58:357-359.

(4.) Edlow JA, Wyer PC. How good is a negative cranial computed tomographic scan result in excluding subarachnoid hemorrhage? Ann Emerg Med. 2000;36: 507-516.

(5.) Fishman R. Composition of the cerebrospinal fluid. In: Cerebrospinal Fluid in Diseases of the Central Nervous System. 2nd ed. Philadelphia, Pa: WB Saunders; 1992:183-252.

(6.) Vermeulen M. Subarachnoid haemorrhage: diagnosis and treatment. J Neurol. 1996;243:496-501.

(7.) van Gijn J. Slip-ups in diagnosis of subarachnoid haemorrhage. Lancet. 1997;349:1492.

(8.) Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry. 1989;52:826-828.

(9.) Soderstrom CE. Diagnostic significance of CSF spectrophotometry and computerized tomography in cerebrovascular disease: a comparative study in 231 cases. Stroke. 1977;8:606-612.

(10.) Judge B. Laboratory Analysis of Xanthochromia in Patients With Suspected Subarachnoid Hemorrhage: A National Survey. Philadelphia, Pa: Scientific Assembly, American College of Emergency Physicians; 2000.

(11.) Mendelow AD, Cartlidge N. Xanthochromia in subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 1990;53:270-271.

(12.) Linn FH, Wijdicks EF, van der Graaf Y, Weerdesteyn-van Vliet FA, Bartelds Al, van Gijn J. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet. 1994;344:590-593.

(13.) Morgenstern L, Luna-Gonzales H, Huber J, et al. Worst headache and subarachnoid hemorrhage: prospective computed tomography and spinal fluid analysis. Ann Emerg Med. 1998;32(pt 1):297-304.

(14.) Marton KI, Gean AD. The spinal tap: a new look at an old test. Ann Intern Med. 1986;104:840-848.

(15.) Eskey An CJ, Ogilvy CS. Fluoroscopy-guided lumbar puncture: decreased frequency of traumatic tap and implications for the assessment of CT-negative acute subarachnoid hemorrhage. AJNR Am J Neuroradiol. 2001;22:571-576.

(16.) Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg. 1996;84:3542.

(17.) Walton J. Subarachnoid Hemorrhage. Edinburgh, Scotland: E & S Livingstone Ltd; 1956:297.

From the Departments of Medicine (Dr Edlow) and Pathology (Dr Horowitz), Harvard Medical School, and Departments of Emergency Medicine (Dr Edlow) and Pathology (Dr Horowitz), Beth Israel Deaconess Medical Center, Boston, Mass; and Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, Ky (Dr Bruner).

Reprints: Jonathan A. Edlow, MD, Department of Emergency Medicine, West Campus-CC-2, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 (e-mail: jedlow@caregroup.harvard.edu).
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No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2002 Gale, Cengage Learning. All rights reserved.

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Author:Edlow, Jonathan A.; Bruner, Kathy S.; Horowitz, Gary L.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Apr 1, 2002
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