Posted by: Chris Cole | July 24, 2014

SAH WARS – Episode V – The Red Cells Strike Back

 

A long time ago in an ED far, far away…

INTRODUCTION

Welcome to another thrilling chapter of the SAH saga!  For those that haven’t been keeping up, here’s the story so far:

  • Clinical decision rules for SAH really suck.
  • Plain CT-brain is really good at finding SAHs.
  • We currently tend to do LPs on patients with headaches suspicious for SAH but who have a negative plain CT-brain.
  • The CSF is analysed for cells, and for xanthochromia.
  • The method used for detecting xanthochromia (visual inspection) is extremely unreliable.
  • Spectrophotometry for xanthochromia would be much better, our lab doesn’t do it, but will if we really push for it.
  • CT-angiogram (CTA)  is really good at finding cerebral aneurysms.
  • CT + CTA leads to, at worst, no more extra or unnecessary DSAs (and subsequent harm) than CT + LP.
  • CT + LP misses at least 4 times as many actual SAHs as CT + CTA.

So, doing an LP for the purposes of trying to detect the presence or absence of xanthochromia, by visual inspection, is not supported by currently available evidence, and is actively derided and advised against both by reputable researchers in the field, and in official guidelines. (See my previous post for details). But, the minions in the laboratory don’t just wave the tube in front of a light and then shake their Magic 8-Ball to decide whether to report it as yellow or not… oh no… they also, quite helpfully, have a look at the CSF under the microscope, and promptly report a RBC and WBC count.

Dr HeWhoShallnotBeNamed (awesome ED boss)  has pointed out that even if one is not a fan of xanthochromia, perhaps the RBC count in the CSF can assist in making or refuting the diagnosis of SAH. And, let’s face it, it’s pretty hard to argue with the logic of looking for blood in the subarachnoid space to answer the question “Is there blood in the subarachnoid space?”.

But, while we may not quite argue with that logic, we shall, I’m afraid, embark on a quest to at least sit down with it over a coffee and have a bit of a robust chat about the situation.

The primary dilemma here is that not all CSF red blood cells are created equal. Some of them were already there when we turned up, and some of them are interlopers, introduced by way of our need to jam a nice long needle through several layers of the patient’s back in order to get to their CSF. In terms of helping make the diagnosis of SAH, it’s the CNS RBCs with native title that we’re after, not the ones that rode in via our needle at the 11th hour. So how do we distinguish between a traumatic tap and a bona fide SAH?

Before delving into the murky waters of looking at the “falling cell count” method of comparing the number of RBCs in the first and last tubes, I want to take a simplistic approach to the situation, in order to outline the pertinent real-world numbers that will form the basis of a more nuanced assessment that takes into account evidence showing that Dr HeWhoShallNotBeNamed is right; the RBC analysis does  make a difference to our diagnostic process. But is that difference big enough? Let’s find out…

Dichotomous RBC count approach

So what happens if we decide that < 5 RBCs in the CSF is negative for SAH, and anything greater than that is a possible SAH that requires further investigation? (This is the normal range / upper limit used in clinical laboratories):

  • 1,000 patients present to ED with a headache suspicious for SAH
  • 100 of them have a SAH (prevalence / pre-test probability in this population is ~10%)
  • 98 of them (at least) will have a +ve plain CT and head off down the DSA/neurosurgery rabbithole
  •  902 of them have a -ve plain CT and go on to have an LP
  • 2 of them have a SAH
  • 180 of them have a traumatic tap performed (typical rate of ~20%)

So out of the ~182 people with a positive LP (based on RBC count), 2 of them really have a SAH, and 180 of them have a false positive due to traumatic tap. This gives a PPV of 2/182 = 1.1%. What does that mean? It means you have to stab around 500 people in the back to find 1 SAH, and in the process you’ll misdiagnose 99 of them with a SAH and send them off for a DSA they don’t need.

As advertised, this is an overly-simplistic approach, but serves to highlight the ballpark figures to be found when using this investigation in a real ED population. Unless we can do something miraculous to improve the situation by considering the specifics of the RBCs we find, this is very likely, a priori,  to be a fairly crappy test for our purposes.

So… are you feeling lucky?  Let’s look for that miracle…

Quantifying the RBC count and the clearance between CSF tubes

There are essentially two parameters considered to be potentially useful in determining whether the blood you found in the CSF represents a SAH, or a bad day with the needle:

  • Absolute RBC count (ARC)
  • Falling RBC count (FRC)

The rationale for the ARC is that one might sensibly expect the RBC count to be higher if a bloody great cerebral aneurysm has just gone KABOOM and pumped a reasonable quantity of blood into the subarachnoid space before anything started to clot, in comparison to the relatively small quantity of blood that might eek its way in along your needle tract.

The logic of the FRC as a discriminator is that the influx of RBCs in a traumatic tap should not be ongoing, and the initial flow of CSF should flush most of the blood out of your needle into the first tube, with subsequently lower RBC counts in the later tubes, particularly the last one (which may be the 3rd or 4th, depending on where you work and which kit you opened). Most commentators suggest a drop of 25 or 30% between the first and last tubes is indicative, or at least strongly suggestive, of a traumatic tap as the source of the RBCs.

ABSOLUTE RBC COUNT (ARC)

The best analysis of the predictive power of the ARC comes from a 2013 study by Amanda Czuczman et al. By virtue of the wonderfully capitalistic private medical system which prevails in the Commonwealth of Massachusetts, the authors were able to retrospectively identify 4,496 consecutive ED patients who’d been billed for an LP, then sift through those to narrow it down to those presenting with headache to the ED who were investigated for SAH. This left them with 280 patients, 26 of whom had a SAH. They had a look at the RBC count in the last tube and found a relationship that is most succinctly tabulated as follows:

  • 0 < RBCs < 100              LR = 0
  • 100 < RBCs < 10,000      LR = 1.6
  • RBCs > 10,000               LR = 6.3

[ Czuczman A et al. 2013 Acad Emerg Med 20(3):247-56. ]

Another group, led by Julie Gorchynski, looked at the same thing back in 2007 in sunny California. They identified 299 ED patients with suspicious headaches who were worked up for possible SAH, had negative plain CT scans, and copped an LP for their trouble. These comprised 288 cases which were finally determined to be traumatic taps, and 11 real SAHs.

Mean RBC counts for tube 1 were:

  • 6,763 for traumatic taps
  • 399,277 for SAH

Mean RBC counts for tube 4 were:

  • 443 for traumatic taps
  • 307,700 for SAH
.
That looks pretty handy as a discriminator, but keep in mind these are average statistics for the two groups. Looking at the individual breakdown, while a (very) strong trend remains, there is enough overlap to give one pause for thought. For example, 18% of SAHs had a RBC count < 5,000 in tube 4. No patients with traumatic tap had a RBC > 10,000 in this study, but 27% of SAHs had a RBC count < 10,000.
The moral of the story is that a very high RBC count (> 10,000) is probably useful as a rule-in test, but using that threshold as a cut-off to rule out SAH is not an option, as you’ll miss ~25% of them. Delving back into the data from the Czuczman 2013 paper, we also find that 16/194 = 8% of traumatic taps had RBC counts > 10,000, so even wielding the ARC as a “rule-in” test has distinct limitations. The Czuczman study did demonstrate a fairly convincing LR of 6.3 for >10,000 RBCs in the final tube, though, and the predictive power of finding a whole bunch of blood in the CSF cannot and should not be dismissed.
.

FALLING RBC COUNT (FRC)

Traditionally it was taught that a drop of more than ~25% in the RBC count between the first and last tubes is strongly suggestive of a traumatic tap, while a more consistent RBC count supports the diagnosis of SAH. it should be noted that this is essentially a consensus opinion, and not based on any actual experimental evidence. Smaller case series exist, for example a paper by Heasley et al. in 2005 published in the American Journal of Neuroradiology reviewed 22 cases of CT-negative severe headaches, found 8 of them had a SAH, and 2 of those SAH patients had >25% clearing of RBCs between the first and last tubes. The two papers I have chosen to cite in this article are the first to properly investigate this question in a rigorous manner, hence their inclusion. The 2013 paper by Czuczman’s group is larger, more rigorous and both designed and reported in a more ED clinican orientated manner, and consequently the most applicable to our clinical practice.

The Gorchynski group’s results are still informative, however. They found that the average fall in RBC between the first and last tubes was 82% in those with traumatic taps, versus 9% in those with SAHs. Again, it must be kept in mind that these are averages, the numbers involved are small, and essentially when trying to make generalised conclusions from data like this, we’re effectively attempting to fit a line or curve through a bunch of sparse, and sometimes very outlying, points. They did find that none of their 11 SAH patients had > 30% RBC clearance across tubes.

The Czuczman group found no useful predictive power in looking at the absolute drop in RBCs across tubes (the ROC curve is a 45 degree straight line, and a perfect example of a completely useless or “coin toss” test). The % drop across tubes, however, was quite predictive, though again not perfect. The sweet spot (maximum diagnostic performance for a dichotomous cut-off) was at 63%, giving an ROC AUC of 0.84 (not too bad at all). The likelihood ratio (LR) for SAH if you had < 63% RBC clearance across tubes was 3.6 (95% CI 2.7-4.7), and only about 0.1 if you had > 63% clearance. This becomes even more impressive, and useful, if one gets excited and combines the absolute number of RBCs with the % drop across tubes, yielding a LR of 24 (7-82) if the patient has both > 10,000 RBCs in the last tube, and a <63% drop in RBCs across tubes. This constitutes what pathologists refer to in private as a Pretty-Good-Test(tm).

PUTTING IT ALL TOGETHER

Okay, so we have this apparently highly predictive test for SAH that requires an LP which, admit it, is kinda fun to do (“Hello everyone. My name is Chris, and I’m a procedure junkie”…). This is AWESOME! (Bonus points if you have seen The Lego Movie and can make it through this paragraph without singing “Everything Is Awesommmmme!” in your head). But alas, as usual, medicine (as with life) is not always as simple as we would like it to be. At the risk of inducing narcoleptic tendencies in those who have made it this far, I feel it is worth re-iterating some basic facts about what it is we do all day when we’re on the floor. We gather information about our patients, and use that information, often at a subconscious level, to modify and refine the probabilities we mentally assign to each of the differential diagnoses we are considering for the patient in question. We often don’t think about this process explicitly, or at least not with numbers attached, with the exception of certain diagnostic pathways, and the Wells/Geneva-XDP-scan decision flowchart is probably the best example of this. While I am not advocating replacing us all with computers implementing a Bayesian approach to diagnosis, there are times when our off-the-cuff generic vibe about what a test (or an examination finding) means can be very different to what it really does mean in real life. In such circumstances, sitting down and explicitly nutting out the numbers can be quite informative. This is one of those times.

Super-dooper important take-home point:

  • Sensitivity, specificity and LR (derived purely from the former two values) are intrinsic properties of the test
  • PPV and NPV are what we need to know about clinically, and they depend on all of the above plus the pre-test probability or prevalence
  • Sometimes an intrinsically crap test can still be a clinically useful discriminator
  • Sometimes an intrinsically good test can be a lousy disciminator when applied clinically
You may recall earlier I did some back of the envelope calculations with a simplified dichotomised RBC count discriminator for diagnosing a SAH on LP. It had a pretty bad PPV (~1%). Let’s see what happens when we apply analysis of RBC count in the last tube, and the % clearance across tubes to our ED population presenting with suspicious headaches, both before and after CT. I’m going to use the LRs from the Czuczman study, because they’re the best we have.
When the CT scanner is broken, or you’re in Cunnamulla…
.
  • 1,000 people present with a headache
  • 100 of them have a SAH
  • You LP everyone, coz that’s just how you roll
  • 20 of them will have a mixture of SAH RBCs + TT RBCs
  • 80 of them will have pure SAH RBCs and a clean tap
  • 180 of them have only TT RBCs from your dodgy tap
  • 720 of them have no RBCs at all

 

You apply the criteria of (a) >10,000 RBCs in the final tube, and (b) <63% clearance across tubes to the bloody taps:

  • A maximally positive result (>10,000 RBCs and <63% clearance) = 73% probability they really have a SAH*
  • A maximally negative results (neither of the above present) = 4% probability they have a SAH*
*you may subtract marks for not showing my working, but this post is long enough… you don’t want to see the maths… trust me.
So in the setting of no available imaging, an LP is a very very useful test to do, as it dramatically alters the probability that your patient has a SAH, and will clearly change your further investigation and management of the patient.
.
But what about when you’re rocking the TCH ED with a 64-slice scanner, and a backup one, just down the corridor??
.
  • 1,000 people present with a headache
  • 100 of them have a SAH
  • 98 of them have a +ve CT and your work here is done, grasshopper
  • 902 have a negative CT and you crack on and LP them
  • 2 of them actually have a SAH
  • 180 have a traumatic tap
Of the LPs you do on this group of 902 patients:
.
  • 2 will have RBCs due purely to SAH
  • 1 will have a mixture of SAH and traumatic RBCs
  • 180 will have only traumatic RBCs
  • 720 will have nothing on microscopy
And your mission, should you choose to accept it, is to tease out which of the 183 bloody CSF samples represent a real live SAH. Applying the diagnostic criteria to this group of patients yields:
.
  • A maximally positive result = 5% probability they really have a SAH
  • A maximally negative result = a problematic result due to the lower bounds of the statistics involved, but near enough to zero to be pretty much zero.

SUMMARY – Crunching the numbers for Real Life(tm)

If we LP everyone who has a negative plain CT-brain in ED:

  •  To find 1 SAH…
  • We send 20 people for a DSA, because they had RBCs that met the +ve criteria outlined above…
  • From 333 people who had any blood at all in their CSF.
  • We had to do 1,667 LPs to find them…
  • And we will cause 1 stroke in the process, because DSA has risks.
So, basically you have to ask yourself if you think it’s reasonable to do 1,667 LPs to find 1 SAH, to cause 1 stroke for every SAH you find, as well as causing an undetermined amount of morbidity (pain, infection, post-LP headache that might need a blood patch, etc). There is also the logistic consideration of tying up ED medical staff and other resources. Not all LPs are easy. Perhaps 50% of the time, a senior clinician will have to step in to do it, and one has to wonder if the resources allocated per diagnosis made or life saved is a reasonable deployment of already overstretched departmental assets.
Again I should stress that life is always more complex than we’d like it to be. If you are chasing or excluding other likely diagnoses, and you want CSF cultures, opening pressures and so on, then clearly an LP is the way to go. But if your only concern if finding a SAH, it is difficult to justify tying up significant departmental resources performing thousands of painful, invasive procedures, laden with its own inherent risks, as well as consigning 19 healthy patients to a more invasive and much riskier procedure, to find that one person in a haystack.
.

SUMMARY OF THE SUMMARY (because we’re ED folk with short attention spans)

If no-one remembers anything else from the ramblings above, please take away this. As counter-intuitive as it may seem, it is, nonetheless, true:
  • A patient presenting to ED with a suspicious headache has around a 10% chance of having a SAH.
  • The same patient with a negative CT-brain, with an LP positive on both RBC criteria has around a 5% chance of SAH.
  • The patient with a negative CT alone has < 2% chance of a SAH.
  • The patient with a negative CT + CTA has < 0.01 % chance of SAH.

SUMMARY OF THE SUMMARY OF THE SUMMARY (for those ED folk who are < 1 hour post-coffee)

  •  Your clinical gestalt with no tests is better at predicting SAH than an LP in a CT-negative patient is.
  • CT + CTA is wayyyyy better than you are
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