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Emergency Medicine Australasia (2015) 27, 267–272
doi: 10.1111/1742-6723.12398
FOR DEBATE
Spectrophotometry, not visual inspection for the detection of xanthochromia in suspected subarachnoid haemorrhage: A debate Kevin H CHU,1,2 Roderick O BISHOP3,4 and Anthony FT BROWN1,2 1 School of Medicine, University of Queensland, Brisbane, Queensland, Australia, 2Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia, 3Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia, and 4Department of Emergency Medicine, Nepean Hospital, Sydney, New South Wales, Australia
The case for Kevin H Chu The measurement of bilirubin in the cerebral spinal fluid (CSF) for the diagnostic work-up of suspected subarachnoid haemorrhage (SAH) is informed by basic science. Following a spontaneous SAH, red blood cells (RBCs) are lysed in the CSF. Free haemoglobin is converted to oxyhaemoglobin, which is then metabolised by macrophages to bilirubin. The former reaction occurs in vitro and in vivo. The latter reaction occurs only in vivo, with bilirubin appearing some 6 to 12 h post-haemorrhage.1 The presence of bilirubin resulting in yellow discolouration of the CSF is the contemporary definition for xanthochromia. 2 The finding of xanthochromia implies a SAH, a condition that is infrequent but has catastrophic morbidity and mortality if missed. 3 A cerebral angiogram in search of a treatable aneurysmal cause is indicated on finding xanthochromia or more specifically on detecting bilirubin in the CSF. Spectrophotometry is a technique for measuring bilirubin in the CSF.4 The usual laboratory analytical techniques cannot be used because bilirubin
appears in too low a concentration. A spectrophotometer measures the light absorption of a material, thus quantifying its presence, analogous to the clinically ubiquitous pulse oximeter. Spectrophotometry is able to detect low concentrations of bilirubin in the CSF. Moreover, it can distinguish between bilirubin and oxyhaemoglobin. It is an objective test that is sensitive for SAH.1 Visual inspection is a subjective test that is insensitive for xanthochromia.5 Unlike spectrophotometry, visual inspection is incapable of detecting low concentrations of bilirubin and differentiating between bilirubin and oxyhaemoglobin. 6 Moreover, its intraobserver and interobserver agreement is poor.7 In sufficient concentrations, oxyhaemoglobin appears orangered whereas bilirubin is yellow. When present, both contribute to the discolouration of the CSF. Visual inspection cannot reliably detect and distinguish between the two. The distinction between oxyhaemoglobin and bilirubin is central to the analysis and interpretation of the CSF. Oxyhaemoglobin appears in both a traumatic lumbar puncture (LP) and following a SAH. A traumatic LP confounds the interpretation of the CSF findings. The
Correspondence: Associate Professor Kevin H Chu, Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, QLD 4029, Australia. Email: [email protected] Kevin H Chu, MBBS, GCBiostat, MS, FACEM, Associate Professor; Roderick O Bishop, MBBS, BSc (Med), MPH, FACEM, Director; Anthony FT Brown, MBChB, FRCP, FRCEM, FACEM, Professor. Accepted 5 February 2015
incidence of a traumatic LP is around 20% when arbitrarily defined as the presence of greater than 400 × 106 RBCs per litre of CSF.8 In conventional teaching, a decreasing RBC count from the first to third or fourth collection tube is indicative of a traumatic LP, whereas a steady RBC count is said to be diagnostic of a SAH. However, a falling RBC count cannot reliably be equated to trauma unless it falls close to zero, because a traumatic LP can occur in the presence of a SAH.9 Bilirubin will only appear following a SAH. Following centrifuge after a traumatic LP, the CSF might look discoloured because of the presence of oxyhaemoglobin and not bilirubin. The presence of bilirubin is the key finding in SAH. CSF bilirubin spectrophotometry is supported by National Guidelines in the UK.10 Proposed in 2003 and revised in 2008, the United Kingdom National External Quality Assurance Service (UKNEQAS) guidelines set out procedures for specimen requirements, transport, handling, analysis and interpretation. The guidelines also articulate the requirements for clinical governance and participation in an appropriate external quality assurance scheme.11 There is no equivalent framework for visual inspection. In Australia, CSF bilirubin spectrophotometry is available, although there is variability in its perceived need. 12 In Queensland, spectrophotometry is provided by Pathology Queensland, which services public hospitals in the state. 13 A spectrophotometer is a piece of desktop printer-sized equipment sitting on the
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laboratory bench. Spectrophotometry is not a technology confined to laboratories or medicine. Hand-held spectrophotometers are available to measure the water content of a vine leaf growing in Australian vineyards for aiding irrigation. 14 Spectrophotometry is apparently not readily available in North American clinical laboratories, thus accounting for their reliance on visual inspection.15 Besides the lack of availability across North America, the other major reported limitation of spectrophotometry is its lack of specificity.8,16 In a recent systematic review of 12 heterogeneous studies, we reported the suboptimalpooled sensitivity of visual inspection (83%) and spectrophotometry (87%), whereas the specificity of visual inspection (96%) appears better than that for spectrophotometry (86%). 17 However, we concluded that heterogeneity in regard to time to LP, spectrophotometry methods and follow up of patients not undergoing cerebral angiography made it impossible to provide a definite conclusion. In our systematic review, subgroup analyses were performed to explore reasons for the heterogeneity in the results. In the two studies that used the UKNEQAS guidelines, their pooled sensitivity and specificity were 93% and 99%, respectively – much more accurate than visual inspection.18,19 The less than 100% sensitivity might be due to the fact that LP was not always performed 12 h or more after headache onset in one of these two studies. 19 Differences in spectrophotometry reported in the studies found for our systematic review included the use of xanthochromic index8,20 and spectrophotometric scanning at discrete rather than continuous wavelengths.16 These methods have been criticised by advocates of the UKNEQAS guidelines.21–23 In keeping with the UKNEQAS guidelines, Pathology Queensland adjusts the CSF bilirubin according to serum bilirubin and CSF protein concentrations. Hyperbilirubinaemia and elevated CSF protein, which bind bilirubin, can cause false positive results and thus lower specificity. The need for this adjustment was not appreciated by older reports on spectrophotometry.
Other causes of false positives are possible but rare.24 An increase in bilirubin and oxyhaemoglobin is consistent with SAH. An isolated increase in bilirubin could be because of elevated serum bilirubin or CSF protein. An isolated increase in oxyhaemoglobin could be because of a traumatic LP. Again, in keeping with the UKNEQAS guidelines, we routinely delay LP until 12 h after headache onset to ensure sufficient time for the formation of bilirubin. Patients are admitted to our Short Stay Ward in the interim. Proponents of visual inspection might argue for an earlier LP relying on a raised RBC count for the diagnosis and attempting to reduce the length of stay in the ED. However, CSF bilirubin is the more reliable method for detecting xanthochromia and hence SAH. Patients requiring LP for suspected SAH are few in number and add little to the overall length of stay of the department. Finally, in a retrospective study of 409 patients who underwent CT head scan and LP, we reported six cases of angiogram-confirmed aneurysmal SAH. All underwent neurosurgical or endovascular intervention. Visual inspection of the CSF supernatant was reported as negative, but spectrophotometry was positive in one of these patients.25 The quantification of bilirubin in the CSF will continue to be a part of the diagnostic work-up of suspected SAH. Currently, the best method for measuring bilirubin in the CSF is spectrophotometry.
The case against Roderick O Bishop The work-up for a patient with suspected SAH who has had a negative CT scan remains controversial.12 LP remains the standard of care for CTnegative patients, at least if the CT was performed after 6 h of onset of the headache. Yet there is wide variation in how to interpret the LP findings,12,26 with uncertainty around the parameters that constitute a ‘positive’ result. Dr Chu argues the case for spectrophotometric examination of CSF being the defined standard. His is an argument based on basic science and all that he says is undoubtably
true. Spectrophotometry is better than visual inspection for identifying bilirubin in the CSF. It is a frequentist’s argument, where sensitivity and specificity of bilirubin in the CSF are taken in isolation. However, clinical diagnosis is Bayesian. The utility and interpretation of clinical information must be guided by what we already know (pre-test probability) as well as the test characteristics. Only a small percentage of patients presenting to an ED with ‘thunderclap’ headache have a SAH. In the Perry et al. study, it is was around 7%.27 The vast majority are diagnosed by CT, so that the chance of having a SAH with a negative CT is around 1%, even if we only LP those patients presenting after 6 h. In the Perry et al. study, just 17 out of 2179 patients presenting after 6 h had a SAH.27 Unless a patient presents many days after the onset of a headache (rare in the ED population), a champagne tap – no cells in the CSF – excludes the diagnosis of SAH, and examination for xanthochromia is pointless. However, the number of RBCs below which a SAH would be excluded has not been defined. Values ranging from 5 × 106 to 100 × 106 or even 400 × 106 RBCs per litre have been used or recommended.28–30 In patients with RBC counts above these numbers, examination for xanthochromia has traditionally been used to identify true subarachnoid bleeding from a traumatic tap. Using the data from the systematic review by Chu et al.,17 let us start by trying to rule out SAH. Apologies for the maths, but that’s Bayes. Assuming a pre-test probability for SAH of 1% in our patients undergoing LP,27 CSF clear by visual inspection would miss 17 SAHs per 10 000 LPs (Table 1). On the other hand, CSF negative for bilirubin by spectrophotometry would miss 13 cases per 10 000 LPs. So spectrophotometry would find four additional cases per 10 000 LPs. The post-test probability of having a SAH is only 0.18% (18 per 10 000 LPs) if the CSF is clear by visual inspection, compared with a probability of 0.15% for a negative spectrophotometric examination. Few clinicians or patients would consider such a small difference of any
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1% 93% 99% 93 0.07 48% 0.07%
Scenario 3
192 9808 10 000 99 9801 9900
1% 87% 86% 6.2 0.15 5.9% 0.15%
Scenario 2
1386 8514 9900
–, negative; +, positive; SAH, subarachnoid haemorrhage.
Scenario 1
1% 83% 96% 21 0.18 17% 0.18% Prevalence or pretest probability Sensitivity Specificity Likelihood ratio + Likelihood ratio – Post-test probability after a positive test Post-test probability after a negative test
396 9504 9900 83 17 100 + – Visual inspection
Absent Present
SAH
479 9521 10 000
Spectrophotometry 1
+ –
87 13 100
Absent Present
SAH
1473 8527 10 000
Spectrophotometry 2
+ –
93 7 100
Absent
SAH
Present
Scenario 3
Spectrophotometry 2
Scenario 2
Spectrophotometry 1
Scenario 1
Visual inspection
TABLE 1. Bayesian analysis using sensitivity and specificity measures for visual inspection and spectrophotometry from Chu’s systematic analysis17 and a 1% prevalence of subarachnoid haemorrhage in CT-negative patients
SPECTROPHOTOMETRY VERSUS VISUAL INSPECTION
clinical significance when considering SAH ‘ruled out’. What about ruling in SAH? Comparing positive test results in the same 10 000 patient cohort, visible xanthochromia in the CSF would find 83 of the 100 patients with SAH, but would be falsely positive in 396 patients. Spectrophotometry would find the additional four patients (87 overall), but would be falsely positive in 1386 patients. For visually xanthochromic CSF, the probability of SAH would be 17% compared with only 5.9% for spectrophotometric identification of bilirubin. Even using the much better test characteristics for spectrophotometry quoted from selected studies by Chu et al.17 (Table 1 scenario 3), spectrophotometry would still miss seven cases per 10 000 LPs, whereas producing a false positive result in 99 patients. What does all this mean? As with all diagnostic testing, using tests with moderate test characteristics in lowrisk patients has limited utility. The marginally better sensitivity (and possibly specificity) of spectrophotometry would only have a chance of making a difference in large cohorts of patients. For the individual emergency physician, or even an individual ED, the numbers of such patients seen over a workinglife time are orders of magnitude lower than used in the examples above. This is confirmed in the unique prospective cohort studies carried out by Perry et al.27,28 With rigorous follow up, they failed to identify any missed SAH using CT and LP with RBC count and visual inspection as their criteria, and imaging for all patients with a positive CSF. One of these studies involved 11 large Canadian EDs over a 10 year period using visual inspection as their test for xanthochromia. A retrospective study by Dupont et al.31 found only one patient in a 10 year period with a SAH in the presence of negative visual xanthochromia. This patient had 20 000 RBCs in her CSF, which in their practice was considered positive and warranted vascular imaging. Similarly, the study by Mark et al.32 documents six patients with negative visual inspection for xanthochromia, having angiographically proven SAH. This was from
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the 21 Northern California Kaiser Permanente EDs over an 11 year period. All six patients had significantly elevated CSF RBCs (range 7282–690 000). This regime – use of RBC count and visible inspection for xanthochromia – represents common practice throughout North America, and given the rate of litigation in the USA, it is hard to believe that any weakness in such a regime has not been exposed by diligent lawyers. In summary, if a LP is used to diagnose SAH after a negative CT scan, absence of both RBCs and visible discolouration is sufficient to rule out SAH. The only unresolved issues with this strategy is the RBC count that constitutes a negative result and in which tube. If the cell count and visual inspection are negative, spectrophotometric examination of CSF for bilirubin delays management, adds costs and risks exposing the patient to further investigations with a miniscule chance of finding additional cases of SAH. If RBCs are present or the CSF supernatant visibly discoloured, further vascular imaging is indicated, because, as Table 1 shows, spectrophotometry does not have the sensitivity to completely rule out SAH. Ask yourself this; if a patient with a good history for SAH has a LP with an RBC count in the 1000s (×106 per litre), are you going to stop there if the spectrophotometry is negative for bilirubin? If the answer is no, don’t bother with the spectrophotometry. If your answer is ‘Yes’, good luck.
Summing up Anthony FT Brown Emergency medicine is not for the faint-hearted, with constant reminders of the perils of a missed diagnosis. Thus, we are berated with data showing that from 0.9% to as high, some say, of 8% patients with an AMI are inadvertently sent home from the ED, leading to greater diagnostic costs, delay in appropriate treatment, a twofold increase in the risk of death and the ever threat of litigation. 33 Similar warnings are said to be true of missing a patient with a pulmonary embolism, with the result that the equipoise in diagnostic testing is slipping to the side of ‘Harm’, certainly in those
in the outpatient setting without physiologic compromise.34 In our attempts to not miss a case, the harm from overtesting leading to contrast-induced nephropathy, cancers from medical imaging and major haemorrhages caused by anticoagulation outweighs the potential benefit, particularly when the scan was false positive, or true positive but with a benign, physiologically harmless clot.34 SAH is another high-risk, highstakes diagnosis, with up to one in five patients with SAH who present with a normal mental status being missed at first ED contact, again leading to increased morbidity and mortality.35,36 Similarly, its investigation is a balance between the benefits and risks around the diagnostic testing paradigm for this uncommon yet potentially lethal condition. Therefore, when dealing with critical diagnoses such as these, it is essential to be clear in our own minds what end-point we will take – that is, what error or miss-rate would be acceptable? Surprisingly little has been published on this risk tolerance, but a survey of Australian, New Zealand, Canadian and United States emergency physicians on the acceptable risk of missing an AMI provides some insight. Almost half accepted a miss-rate of 1% or less, with a majority accepting a miss-rate of 0.5% or less. 37 This equates to the expectation for diagnostic strategies to achieve a sensitivity of 99% or higher, but not 100% as it is impossible to entirely exclude risk, and irrational, uneconomic and unhelpful to expect to.38 Similarly, when considering the patient with an acute headache and the role of a clinical decision rule to rule out SAH, a survey of emergency physicians from the same four countries deemed that the median sensitivity required was 99% (interquartile range [IQR] 98–99%).39 Armed and now comfy with this concept of diagnostic uncertainty and risk tolerance, where do the arguments of Chu and Bishop leave us on the ‘net health value’ approach to ruling out SAH? At first glance, apparently not all that well – with visual inspection having 83% sensitivity, and for spectrophotometry 87– 93% sensitivity. 17–19 However, as Bishop points out, it is imperative to
consider the pre-test probability of SAH in patients who end up needing a LP, which is around 1% in those who are CT negative.27 Now both alternatives look rather good, as with a clear ‘negative’ visual inspection the post-test probability of SAH has dropped to 0.18% (or less than 1 in 500), and with negative spectrophotometry the post-test probability at worst is a mere 0.15%, and at best 0.07% (or less than 1 in a thousand). Thus, both approaches easily satisfy our expectation of a sub 0.5% error or miss-rate. In addition, the clinical population we are talking about who present with sudden headache and are neurologically intact and have a negative CT scan appear to do well anyway. Even in the early days of CT scanning in the 1980s, if the patient with a negative CT did in fact have an aneurysmal SAH, the mortality was just 2.8% at 6 months.32 Next, turning our attention to ruling in SAH, visual inspection with a specificity of 96% sits midway in the range of spectrophotometry specificities from 86% to 99%.17–19 This means that both tests will still over-read, that is, even after a positive test with visual inspection, 83% of patients still do not have SAH, and with spectrophotometry 52% (best case) to 94% do not have SAH. Although it is harder to quantify the downside to these false positives, they come at the expense of needing additional testing, such as cerebral angiography, plus increased patient concern. So how do we decide? There is clearly no right or wrong answer, but an approach that is a balance between what each test is actually telling you, the clinician, and what you and your patient wish to accept. Shared decisionmaking as the apex of patient-centred care is increasingly being expected in clinical practice.40 The patient, who remember is neurologically intact albeit possibly with some degree of headache, can be informed of the meaning of whichever test is chosen, and be part of the decision. There are standardised ways of expressing medical risk in terms of everyday occurrences, such as the Calman Chart, or by framing it pictorially, for instance with smiling faces or grimaces depicting number needed to treat/harm.41
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The variation in practice between North America (visual inspection) and the UK, plus some of continental Europe (spectrophotometry), likely reflects differences in the availability of imaging technologies, different practice patterns and healthcare reimbursement systems, and different medicolegal environments.42 It is unlikely that as laboratory automation continues on, there will be a shift in North America from visual inspection to a UK-style manual spectrophotometric method of testing. The questionable value of the subtle differences in their performance in a population already at a low risk of SAH appears to support the status quo.
Competing interests KHC is a section editor for Emergency Medicine Australasia and is supported by a grant from the Queensland Emergency Medicine Research Foundation. AFTB is the immediate past Editorin-Chief of Emergency Medicine Australasia.
References 1. Petzold A, Sharpe LT, Keir G. Spectrophotometry for cerebrospinal fluid pigment analysis. Neurocrit. Care 2006; 4: 153–62. 2. Chalmers AH, Kiley M. Detection of xanthochromia in cerebrospinal fluid. Clin. Chem. 1998; 44: 1740–2. 3. Vermeulen MJ, Schull MJ. Missed diagnosis of subarachnoid hemorrhage in the emergency department. Stroke 2007; 38: 1216–21. 4. Beetham R. CSF spectrophotometry for bilirubin – why and how? Scand. J. Clin. Lab. Invest. 2009; 69: 1–7. 5. Petzold A, Keir G, Sharpe LT. Spectrophotometry for xanthochromia. N. Engl. J. Med. 2004; 351: 1695–6. 6. Petzold A, Keir G, Sharpe TL. Why human color vision cannot reliably detect cerebrospinal fluid xanthochromia. Stroke 2005; 36: 1295–7. 7. Marshman LA, Duell R, Rudd D, Johnston R, Faris C. Intraobserver and interobserver agreement in visual inspection for xanthochromia:
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implications for subarachnoid hemorrhage diagnosis, computed tomography validation studies, and the walton rule. Neurosurgery 2014; 74: 395–400. Wood MJ, Dimeski G, Nowitzke AM. CSF spectrophotometry in the diagnosis and exclusion of spontaneous subarachnoid haemorrhage. J. Clin. Neurosci. 2005; 12: 142–6. Shah KH, Edlow JA. Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage. J. Emerg. Med. 2002; 23: 67–74. Cruickshank A, Auld P, Beetham R et al. Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann. Clin. Biochem. 2008; 45: 238–44. Beetham R, Egner W, Patel D. The UKNEQAS scheme for cerebrospinal fluid haem pigments: a paradigm for service improvement. Ann. Clin. Biochem. 2011; 48: 489–97. Rogers A, Furyk J, Banks C, Chu K. Diagnosis of subarachnoid haemorrhage: a survey of Australasian emergency physicians and trainees. Emerg. Med. Australas. 2014; 26: 468–73. Queensland Health. Pathology Queensland – available tests. 2014 [Cited 22 Apr 2015.] Available from URL: http://www.health.qld.gov.au/ qhcss/testlist/testlist.asp Australian Broadcasting Corporation. Catalyst Technoviticulture. 7 March 2013. [Cited 22 Apr 2015.] Available from URL: http:// www.abc.net.au/catalyst/stories/ 3708366.htm Edlow JA, Bruner KS, Horowitz GL. Xanthochromia. Arch. Pathol. Lab. Med. 2002; 126: 413–15. Perry JJ, Sivilotti ML, Stiell IG et al. Should spectrophotometry be used to identify xanthochromia in the cerebrospinal fluid of alert patients suspected of having subarachnoid hemorrhage? Stroke 2006; 37: 2467– 72. Chu K, Hann A, Greenslade J, Williams J, Brown A. Spectrophotometry or visual inspection to most reliably detect xanthochromia in subarachnoid hemorrhage: systematic review. Ann. Emerg. Med. 2014; 64: 257–64. Alons IM, Verheul RJ, Ponjee GA, Jellema K. Optimizing blood pigment
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analysis in cerebrospinal fluid for the diagnosis of subarachnoid haemorrhage – a practical approach. Eur. J. Neurol. 2013; 20: 193–7. Chao CY, 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. Foot C, Staib A. How valuable is a lumbar puncture in the management of patients with suspected subarachnoid haemorrhage? Emerg. Med. 2001; 13: 326–32. Watson ID, Beetham R, Keir G et al. Cerebrospinal fluid spectrophotometry of bilirubin, not the Xanthochromic Index, for the detection of CT-negative sub-arachnoid haemorrhage. J. Clin. Neurosci. 2007; 14: 608–9. Beetham R, Fahie-Wilson M, Holbrook I et al. How valuable is a lumbar puncture in the management of patients with suspected subarachnoid haemorrhage? Emerg. Med. (Fremantle) 2002; 14: 195, author reply 6. Beetham R, Lhatoo S. Should spectrophotometry be used to identify xanthochromia in the cerebrospinal fluid of alert patients suspected of having subarachnoid hemorrhage? Stroke 2007; 38: e86, author reply e7. Aisiku I, Edlow J, Goldstein J, Thomas L. An evidence-based approach to diagnosis and management of subarachnoid hemorrhage in the emergency department. Emerg. Med. Pract. 2014; 16: 29. Hann A, Chu K, Greenslade J, Williams J, Brown A. Benefit of cerebrospinal fluid spectrophotometry in the assessment of CT scan negative suspected subarachnoid haemorrhage: a diagnostic accuracy study. J. Clin. Neurosci. 2015; 22: 173–9. Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N. Engl. J. Med. 2000; 342: 29–36. Perry JJ, Stiell IG, Sivilotti ML et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ 2011; 343: d4277.
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28. Perry JJ, Spacek A, Forbes M et al. Is the combination of negative computed tomography result and negative lumbar puncture result sufficient to rule out subarachnoid hemorrhage? Ann. Emerg. Med. 2008; 51: 707–13. 29. Czuczman AD, Thomas LE, Boulanger AB et al. Interpreting red blood cells in lumbar puncture: distinguishing true subarachnoid hemorrhage from traumatic tap. Acad. Emerg. Med. 2013; 20: 247–56. 30. Shah KH, Richard KM, Nicholas S, Edlow JA. Incidence of traumatic lumbar puncture. Acad. Emerg. Med. 2003; 10: 151–4. 31. Dupont SA, Wijdicks EF, Manno EM, Rabinstein AA. Thunderclap headache and normal computed tomographic results: value of cerebrospinal fluid analysis. Mayo Clin. Proc. 2008; 83: 1326–31. 32. Mark DG, Hung YY, Offerman SR et al. Nontraumatic subarachnoid hemorrhage in the setting of nega-
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tive cranial computed tomography results: external validation of a clinical and imaging prediction rule. Ann. Emerg. Med. 2013; 62: 1–10.e1. Moy E, Barrett M, Coffey R, Hines AL, Newman-Toker DE. Missed diagnoses of acute myocardial infarction in the emergency department: variation by patient and facility characteristics. Diagnosis 2015; 2: 29– 40. Newman D, Schriger D. Rethinking testing for pulmonary embolism: less is more. Ann. Emerg. Med. 2011; 57: 622–7. Newman-Toker D, Edlow J. Highstakes diagnostic decision rules for serious disorders. The Ottawa Subarachnoid Hemorrhage Rule. JAMA 2013; 310: 1237–9. Kowalski R, Claassen J, Kreiter K et al. Initial misdiagnosis and outcome after subarachnoid hemorrhage. JAMA 2004; 291: 866–9. Than M, Herbert M, Flaws D et al. What is an acceptable risk of major
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adverse cardiac event in chest pain patients soon after discharge from the Emergency Department? Int. J. Cardiol. 2013; 166: 752–4. Goodacre S. Safe discharge: an irrational, unhelpful and unachievable concept. Emerg. Med. J. 2006; 23: 753–5. Perry J, Eagles D, Clement C et al. An international study of emergency physicians’ practice for acute headache management and the need for a clinical decision rule. CJEM 2009; 11: 516–22. Barry M, Edgman-Levitan S. Shared decision making – the pinnacle of patient-centered care. N. Engl. J. Med. 2012; 366: 780–1. Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical data into meaningful pictures. BMJ 2002; 324: 827–30. Sandhaus L. CSF spectrophotometry in questionable SAH. Neurocrit. Care 2006; 4: 101–2.
© 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Emergency Medicine Australasia (2015) 27, 267–272
doi: 10.1111/1742-6723.12398
FOR DEBATE
Spectrophotometry, not visual inspection for the detection of xanthochromia in suspected subarachnoid haemorrhage: A debate Kevin H CHU,1,2 Roderick O BISHOP3,4 and Anthony FT BROWN1,2 1 School of Medicine, University of Queensland, Brisbane, Queensland, Australia, 2Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia, 3Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia, and 4Department of Emergency Medicine, Nepean Hospital, Sydney, New South Wales, Australia
The case for Kevin H Chu The measurement of bilirubin in the cerebral spinal fluid (CSF) for the diagnostic work-up of suspected subarachnoid haemorrhage (SAH) is informed by basic science. Following a spontaneous SAH, red blood cells (RBCs) are lysed in the CSF. Free haemoglobin is converted to oxyhaemoglobin, which is then metabolised by macrophages to bilirubin. The former reaction occurs in vitro and in vivo. The latter reaction occurs only in vivo, with bilirubin appearing some 6 to 12 h post-haemorrhage.1 The presence of bilirubin resulting in yellow discolouration of the CSF is the contemporary definition for xanthochromia. 2 The finding of xanthochromia implies a SAH, a condition that is infrequent but has catastrophic morbidity and mortality if missed. 3 A cerebral angiogram in search of a treatable aneurysmal cause is indicated on finding xanthochromia or more specifically on detecting bilirubin in the CSF. Spectrophotometry is a technique for measuring bilirubin in the CSF.4 The usual laboratory analytical techniques cannot be used because bilirubin
appears in too low a concentration. A spectrophotometer measures the light absorption of a material, thus quantifying its presence, analogous to the clinically ubiquitous pulse oximeter. Spectrophotometry is able to detect low concentrations of bilirubin in the CSF. Moreover, it can distinguish between bilirubin and oxyhaemoglobin. It is an objective test that is sensitive for SAH.1 Visual inspection is a subjective test that is insensitive for xanthochromia.5 Unlike spectrophotometry, visual inspection is incapable of detecting low concentrations of bilirubin and differentiating between bilirubin and oxyhaemoglobin. 6 Moreover, its intraobserver and interobserver agreement is poor.7 In sufficient concentrations, oxyhaemoglobin appears orangered whereas bilirubin is yellow. When present, both contribute to the discolouration of the CSF. Visual inspection cannot reliably detect and distinguish between the two. The distinction between oxyhaemoglobin and bilirubin is central to the analysis and interpretation of the CSF. Oxyhaemoglobin appears in both a traumatic lumbar puncture (LP) and following a SAH. A traumatic LP confounds the interpretation of the CSF findings. The
Correspondence: Associate Professor Kevin H Chu, Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, QLD 4029, Australia. Email: [email protected] Kevin H Chu, MBBS, GCBiostat, MS, FACEM, Associate Professor; Roderick O Bishop, MBBS, BSc (Med), MPH, FACEM, Director; Anthony FT Brown, MBChB, FRCP, FRCEM, FACEM, Professor. Accepted 5 February 2015
incidence of a traumatic LP is around 20% when arbitrarily defined as the presence of greater than 400 × 106 RBCs per litre of CSF.8 In conventional teaching, a decreasing RBC count from the first to third or fourth collection tube is indicative of a traumatic LP, whereas a steady RBC count is said to be diagnostic of a SAH. However, a falling RBC count cannot reliably be equated to trauma unless it falls close to zero, because a traumatic LP can occur in the presence of a SAH.9 Bilirubin will only appear following a SAH. Following centrifuge after a traumatic LP, the CSF might look discoloured because of the presence of oxyhaemoglobin and not bilirubin. The presence of bilirubin is the key finding in SAH. CSF bilirubin spectrophotometry is supported by National Guidelines in the UK.10 Proposed in 2003 and revised in 2008, the United Kingdom National External Quality Assurance Service (UKNEQAS) guidelines set out procedures for specimen requirements, transport, handling, analysis and interpretation. The guidelines also articulate the requirements for clinical governance and participation in an appropriate external quality assurance scheme.11 There is no equivalent framework for visual inspection. In Australia, CSF bilirubin spectrophotometry is available, although there is variability in its perceived need. 12 In Queensland, spectrophotometry is provided by Pathology Queensland, which services public hospitals in the state. 13 A spectrophotometer is a piece of desktop printer-sized equipment sitting on the
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laboratory bench. Spectrophotometry is not a technology confined to laboratories or medicine. Hand-held spectrophotometers are available to measure the water content of a vine leaf growing in Australian vineyards for aiding irrigation. 14 Spectrophotometry is apparently not readily available in North American clinical laboratories, thus accounting for their reliance on visual inspection.15 Besides the lack of availability across North America, the other major reported limitation of spectrophotometry is its lack of specificity.8,16 In a recent systematic review of 12 heterogeneous studies, we reported the suboptimalpooled sensitivity of visual inspection (83%) and spectrophotometry (87%), whereas the specificity of visual inspection (96%) appears better than that for spectrophotometry (86%). 17 However, we concluded that heterogeneity in regard to time to LP, spectrophotometry methods and follow up of patients not undergoing cerebral angiography made it impossible to provide a definite conclusion. In our systematic review, subgroup analyses were performed to explore reasons for the heterogeneity in the results. In the two studies that used the UKNEQAS guidelines, their pooled sensitivity and specificity were 93% and 99%, respectively – much more accurate than visual inspection.18,19 The less than 100% sensitivity might be due to the fact that LP was not always performed 12 h or more after headache onset in one of these two studies. 19 Differences in spectrophotometry reported in the studies found for our systematic review included the use of xanthochromic index8,20 and spectrophotometric scanning at discrete rather than continuous wavelengths.16 These methods have been criticised by advocates of the UKNEQAS guidelines.21–23 In keeping with the UKNEQAS guidelines, Pathology Queensland adjusts the CSF bilirubin according to serum bilirubin and CSF protein concentrations. Hyperbilirubinaemia and elevated CSF protein, which bind bilirubin, can cause false positive results and thus lower specificity. The need for this adjustment was not appreciated by older reports on spectrophotometry.
Other causes of false positives are possible but rare.24 An increase in bilirubin and oxyhaemoglobin is consistent with SAH. An isolated increase in bilirubin could be because of elevated serum bilirubin or CSF protein. An isolated increase in oxyhaemoglobin could be because of a traumatic LP. Again, in keeping with the UKNEQAS guidelines, we routinely delay LP until 12 h after headache onset to ensure sufficient time for the formation of bilirubin. Patients are admitted to our Short Stay Ward in the interim. Proponents of visual inspection might argue for an earlier LP relying on a raised RBC count for the diagnosis and attempting to reduce the length of stay in the ED. However, CSF bilirubin is the more reliable method for detecting xanthochromia and hence SAH. Patients requiring LP for suspected SAH are few in number and add little to the overall length of stay of the department. Finally, in a retrospective study of 409 patients who underwent CT head scan and LP, we reported six cases of angiogram-confirmed aneurysmal SAH. All underwent neurosurgical or endovascular intervention. Visual inspection of the CSF supernatant was reported as negative, but spectrophotometry was positive in one of these patients.25 The quantification of bilirubin in the CSF will continue to be a part of the diagnostic work-up of suspected SAH. Currently, the best method for measuring bilirubin in the CSF is spectrophotometry.
The case against Roderick O Bishop The work-up for a patient with suspected SAH who has had a negative CT scan remains controversial.12 LP remains the standard of care for CTnegative patients, at least if the CT was performed after 6 h of onset of the headache. Yet there is wide variation in how to interpret the LP findings,12,26 with uncertainty around the parameters that constitute a ‘positive’ result. Dr Chu argues the case for spectrophotometric examination of CSF being the defined standard. His is an argument based on basic science and all that he says is undoubtably
true. Spectrophotometry is better than visual inspection for identifying bilirubin in the CSF. It is a frequentist’s argument, where sensitivity and specificity of bilirubin in the CSF are taken in isolation. However, clinical diagnosis is Bayesian. The utility and interpretation of clinical information must be guided by what we already know (pre-test probability) as well as the test characteristics. Only a small percentage of patients presenting to an ED with ‘thunderclap’ headache have a SAH. In the Perry et al. study, it is was around 7%.27 The vast majority are diagnosed by CT, so that the chance of having a SAH with a negative CT is around 1%, even if we only LP those patients presenting after 6 h. In the Perry et al. study, just 17 out of 2179 patients presenting after 6 h had a SAH.27 Unless a patient presents many days after the onset of a headache (rare in the ED population), a champagne tap – no cells in the CSF – excludes the diagnosis of SAH, and examination for xanthochromia is pointless. However, the number of RBCs below which a SAH would be excluded has not been defined. Values ranging from 5 × 106 to 100 × 106 or even 400 × 106 RBCs per litre have been used or recommended.28–30 In patients with RBC counts above these numbers, examination for xanthochromia has traditionally been used to identify true subarachnoid bleeding from a traumatic tap. Using the data from the systematic review by Chu et al.,17 let us start by trying to rule out SAH. Apologies for the maths, but that’s Bayes. Assuming a pre-test probability for SAH of 1% in our patients undergoing LP,27 CSF clear by visual inspection would miss 17 SAHs per 10 000 LPs (Table 1). On the other hand, CSF negative for bilirubin by spectrophotometry would miss 13 cases per 10 000 LPs. So spectrophotometry would find four additional cases per 10 000 LPs. The post-test probability of having a SAH is only 0.18% (18 per 10 000 LPs) if the CSF is clear by visual inspection, compared with a probability of 0.15% for a negative spectrophotometric examination. Few clinicians or patients would consider such a small difference of any
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1% 93% 99% 93 0.07 48% 0.07%
Scenario 3
192 9808 10 000 99 9801 9900
1% 87% 86% 6.2 0.15 5.9% 0.15%
Scenario 2
1386 8514 9900
–, negative; +, positive; SAH, subarachnoid haemorrhage.
Scenario 1
1% 83% 96% 21 0.18 17% 0.18% Prevalence or pretest probability Sensitivity Specificity Likelihood ratio + Likelihood ratio – Post-test probability after a positive test Post-test probability after a negative test
396 9504 9900 83 17 100 + – Visual inspection
Absent Present
SAH
479 9521 10 000
Spectrophotometry 1
+ –
87 13 100
Absent Present
SAH
1473 8527 10 000
Spectrophotometry 2
+ –
93 7 100
Absent
SAH
Present
Scenario 3
Spectrophotometry 2
Scenario 2
Spectrophotometry 1
Scenario 1
Visual inspection
TABLE 1. Bayesian analysis using sensitivity and specificity measures for visual inspection and spectrophotometry from Chu’s systematic analysis17 and a 1% prevalence of subarachnoid haemorrhage in CT-negative patients
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clinical significance when considering SAH ‘ruled out’. What about ruling in SAH? Comparing positive test results in the same 10 000 patient cohort, visible xanthochromia in the CSF would find 83 of the 100 patients with SAH, but would be falsely positive in 396 patients. Spectrophotometry would find the additional four patients (87 overall), but would be falsely positive in 1386 patients. For visually xanthochromic CSF, the probability of SAH would be 17% compared with only 5.9% for spectrophotometric identification of bilirubin. Even using the much better test characteristics for spectrophotometry quoted from selected studies by Chu et al.17 (Table 1 scenario 3), spectrophotometry would still miss seven cases per 10 000 LPs, whereas producing a false positive result in 99 patients. What does all this mean? As with all diagnostic testing, using tests with moderate test characteristics in lowrisk patients has limited utility. The marginally better sensitivity (and possibly specificity) of spectrophotometry would only have a chance of making a difference in large cohorts of patients. For the individual emergency physician, or even an individual ED, the numbers of such patients seen over a workinglife time are orders of magnitude lower than used in the examples above. This is confirmed in the unique prospective cohort studies carried out by Perry et al.27,28 With rigorous follow up, they failed to identify any missed SAH using CT and LP with RBC count and visual inspection as their criteria, and imaging for all patients with a positive CSF. One of these studies involved 11 large Canadian EDs over a 10 year period using visual inspection as their test for xanthochromia. A retrospective study by Dupont et al.31 found only one patient in a 10 year period with a SAH in the presence of negative visual xanthochromia. This patient had 20 000 RBCs in her CSF, which in their practice was considered positive and warranted vascular imaging. Similarly, the study by Mark et al.32 documents six patients with negative visual inspection for xanthochromia, having angiographically proven SAH. This was from
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the 21 Northern California Kaiser Permanente EDs over an 11 year period. All six patients had significantly elevated CSF RBCs (range 7282–690 000). This regime – use of RBC count and visible inspection for xanthochromia – represents common practice throughout North America, and given the rate of litigation in the USA, it is hard to believe that any weakness in such a regime has not been exposed by diligent lawyers. In summary, if a LP is used to diagnose SAH after a negative CT scan, absence of both RBCs and visible discolouration is sufficient to rule out SAH. The only unresolved issues with this strategy is the RBC count that constitutes a negative result and in which tube. If the cell count and visual inspection are negative, spectrophotometric examination of CSF for bilirubin delays management, adds costs and risks exposing the patient to further investigations with a miniscule chance of finding additional cases of SAH. If RBCs are present or the CSF supernatant visibly discoloured, further vascular imaging is indicated, because, as Table 1 shows, spectrophotometry does not have the sensitivity to completely rule out SAH. Ask yourself this; if a patient with a good history for SAH has a LP with an RBC count in the 1000s (×106 per litre), are you going to stop there if the spectrophotometry is negative for bilirubin? If the answer is no, don’t bother with the spectrophotometry. If your answer is ‘Yes’, good luck.
Summing up Anthony FT Brown Emergency medicine is not for the faint-hearted, with constant reminders of the perils of a missed diagnosis. Thus, we are berated with data showing that from 0.9% to as high, some say, of 8% patients with an AMI are inadvertently sent home from the ED, leading to greater diagnostic costs, delay in appropriate treatment, a twofold increase in the risk of death and the ever threat of litigation. 33 Similar warnings are said to be true of missing a patient with a pulmonary embolism, with the result that the equipoise in diagnostic testing is slipping to the side of ‘Harm’, certainly in those
in the outpatient setting without physiologic compromise.34 In our attempts to not miss a case, the harm from overtesting leading to contrast-induced nephropathy, cancers from medical imaging and major haemorrhages caused by anticoagulation outweighs the potential benefit, particularly when the scan was false positive, or true positive but with a benign, physiologically harmless clot.34 SAH is another high-risk, highstakes diagnosis, with up to one in five patients with SAH who present with a normal mental status being missed at first ED contact, again leading to increased morbidity and mortality.35,36 Similarly, its investigation is a balance between the benefits and risks around the diagnostic testing paradigm for this uncommon yet potentially lethal condition. Therefore, when dealing with critical diagnoses such as these, it is essential to be clear in our own minds what end-point we will take – that is, what error or miss-rate would be acceptable? Surprisingly little has been published on this risk tolerance, but a survey of Australian, New Zealand, Canadian and United States emergency physicians on the acceptable risk of missing an AMI provides some insight. Almost half accepted a miss-rate of 1% or less, with a majority accepting a miss-rate of 0.5% or less. 37 This equates to the expectation for diagnostic strategies to achieve a sensitivity of 99% or higher, but not 100% as it is impossible to entirely exclude risk, and irrational, uneconomic and unhelpful to expect to.38 Similarly, when considering the patient with an acute headache and the role of a clinical decision rule to rule out SAH, a survey of emergency physicians from the same four countries deemed that the median sensitivity required was 99% (interquartile range [IQR] 98–99%).39 Armed and now comfy with this concept of diagnostic uncertainty and risk tolerance, where do the arguments of Chu and Bishop leave us on the ‘net health value’ approach to ruling out SAH? At first glance, apparently not all that well – with visual inspection having 83% sensitivity, and for spectrophotometry 87– 93% sensitivity. 17–19 However, as Bishop points out, it is imperative to
consider the pre-test probability of SAH in patients who end up needing a LP, which is around 1% in those who are CT negative.27 Now both alternatives look rather good, as with a clear ‘negative’ visual inspection the post-test probability of SAH has dropped to 0.18% (or less than 1 in 500), and with negative spectrophotometry the post-test probability at worst is a mere 0.15%, and at best 0.07% (or less than 1 in a thousand). Thus, both approaches easily satisfy our expectation of a sub 0.5% error or miss-rate. In addition, the clinical population we are talking about who present with sudden headache and are neurologically intact and have a negative CT scan appear to do well anyway. Even in the early days of CT scanning in the 1980s, if the patient with a negative CT did in fact have an aneurysmal SAH, the mortality was just 2.8% at 6 months.32 Next, turning our attention to ruling in SAH, visual inspection with a specificity of 96% sits midway in the range of spectrophotometry specificities from 86% to 99%.17–19 This means that both tests will still over-read, that is, even after a positive test with visual inspection, 83% of patients still do not have SAH, and with spectrophotometry 52% (best case) to 94% do not have SAH. Although it is harder to quantify the downside to these false positives, they come at the expense of needing additional testing, such as cerebral angiography, plus increased patient concern. So how do we decide? There is clearly no right or wrong answer, but an approach that is a balance between what each test is actually telling you, the clinician, and what you and your patient wish to accept. Shared decisionmaking as the apex of patient-centred care is increasingly being expected in clinical practice.40 The patient, who remember is neurologically intact albeit possibly with some degree of headache, can be informed of the meaning of whichever test is chosen, and be part of the decision. There are standardised ways of expressing medical risk in terms of everyday occurrences, such as the Calman Chart, or by framing it pictorially, for instance with smiling faces or grimaces depicting number needed to treat/harm.41
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The variation in practice between North America (visual inspection) and the UK, plus some of continental Europe (spectrophotometry), likely reflects differences in the availability of imaging technologies, different practice patterns and healthcare reimbursement systems, and different medicolegal environments.42 It is unlikely that as laboratory automation continues on, there will be a shift in North America from visual inspection to a UK-style manual spectrophotometric method of testing. The questionable value of the subtle differences in their performance in a population already at a low risk of SAH appears to support the status quo.
Competing interests KHC is a section editor for Emergency Medicine Australasia and is supported by a grant from the Queensland Emergency Medicine Research Foundation. AFTB is the immediate past Editorin-Chief of Emergency Medicine Australasia.
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