You’re Damn Screwed on Ticagrelor

If you’re unlucky enough to suffer intracranial bleeding, your unluckiness is compounded if you’re concurrently taking any sort of anticoagulation.  Some agents have relatively-effective reversal options – typically prothrombin concentrate complexes or fresh frozen plasma.  Anti-platelet agents, however, tend to irreversibly bind and inactivate platelets – and the only theoretical reversal strategy is transfusion with new, unblemished platelets.

That definitely won’t work for ticagrelor.

This brief letter in the NEJM details the unfortunate case of a man suffering a hemorrhagic transformation following a stroke while on ticagrelor.  As part his treatment, these authors transfused the patient a total of 17 units of platelets.  After said transfusion, the platelet-reactivity index barely rose from 0% to approximately 10% immediately following the transfusion – but then returned to 0% an hour later, and remained unchanged at 0% seven hours later when rechecked.  As you might expect, with 0% platelet activity, the patient expired as a result of his intracranial bleeding.

If you can manage not to waste blood products in such futile action, please do so.  Also, beware!

“Inefficacy of Platelet Transfusion to Reverse Ticagrelor”
http://www.ncbi.nlm.nih.gov/pubmed/25564918

The Wholesale Revision of ACEP’s tPA Clinical Policy

ACEP has published a draft version of their new Clinical Policy statement regarding the use of IV tPA in acute ischemic stroke.  As before, the policy statement aims to answer the questions:

(1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?
(2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

Most readers of this blog are familiar with the mild uproar the previous version caused, and this revision opens by stating “changes to the ACEP clinical policies development process have been implemented, the grading forms used to rate published research have continued to evolve, and newer research articles have been published.”  Left unsaid, in presumably a bit of diplomacy, were the conflicts of interest befouling the prior work.  Notably absent from this work is any involvement from the American Academy of Neurology.

What’s new, with a new methodology-focused rather than conflicted-expert-opinion approach?  Most obviously, there’s a new Level A recommendation – focused on the only consistent finding across all tPA trials: clinicians must consider a 7% incidence of symptomatic intracranial hemorrhage, compared with 1% in the placebo cohorts.  The previously Level A recommendation to treat within 3 hours has been downgraded to Level B.  Treatment up to 4.5 hours remains Level B.  Finally, a new Level C recommendation includes a consensus statement recommending shared decision-making between the patient and a member of the healthcare team regarding the potential benefits and harms.

Most of the reaction on Twitter has been, essentially, a declaration of victory.  And, in a sense, it is certainly a powerful statement regarding the ability for like-minded patient advocates and evidence purists to coalesce through alternative media and initiate a major change in policy.  To critique this new effort is a bit of punishing the good for lack of manifesting perfect, but there are a number of oddities worth providing feedback to the writing committee:

  • The authors provide a curious statement:  “The 2012 IV tPA clinical policy recommendation to ‘offer’ tPA to patients presenting with acute ischemic stroke within 3 hours of symptom onset was consistent with other national guidelines. Unfortunately, the essence of the term ‘offer’ may have been lost to readers and has therefore been avoided in this revision.”  I rather find “offer” a lovely term, in the sense it expresses a cooperative process for proceeding forward with a mutually agreed upon treatment strategy.  Rather than discard the term, clarification might have been reasonable.
  • They mention ATLANTIS as Class III evidence with regard to the 3-4.5 hour question.  I can see how its classification may be downgraded given the multiple protocol revisions.  That said, its inability to find a treatment benefit in spite of extensive sponsor involvement ought be a more powerful negative weighting than currently acknowledged.  Given the biases favoring the treatment group in ECASS III (given a Class II evidence label), the cumulative evidence probably does not support a Level B recommendation for the 3-4.5 hour window.
  • One of my Australian colleagues in private communication brings up a small letter from Bradley Shy, previously covered on this blog, mentioning a statistical change to ECASS III.  This statement could acknowledge this post-publication correction and its implications regarding the aforementioned imbalance between groups.
  • The authors fail to acknowledge the heterogeneity of acute ischemic stroke syndromes and patient substrates, and the utter paucity of individualized risk or benefit assessment tools – in no small consequence of the small sample sizes of the few trials rated as Class I or Class II evidence.  This is a powerful platform with which to state clinical equipoise exists for continued placebo-controlled randomization.  As we see from the endovascular trials, the acute recanalization rate of IV tPA is as low as 40% – with many patients re-occluding following completion of the infusion.  Patients need to be selected less broadly with respect to likelihood of benefit compared with supportive care.  I believe tPA helps some patients, but it should be a goal to dramatically reduce the costs and collateral damage associated with rushing to treat mimics and patients without a favorable balance of risks and benefits.  For these authors to recommend treatment in “carefully selected patients” and “shared decision-making”, more guidance should be provided – and absent the evidence to support such guidance, they should be calling for more trials!

The comment period is open until March 13, 2015.

“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department DRAFT”
http://www.acep.org/Clinical-Policy-Comment-form-Intravenous-tPA/

Addendum 01/18/2015:
The SAEM EBM interest group is compiling comments on the evidence for feedback to the SAEM board of directors.  These are my additional comments after having had additional time to digest:

  • I agree with sICH as a Level A recommendation.  Both RCTs and observational registries tend to support such a recommendation.  Whether the pooled risk estimates are usable in knowledge translation to individual patients is less clear.  The risk of sICH is highly variable depending on individual patient substrate.  There are several risk stratification instruments described in the literature, but none are specifically recommended/endorsed/prospectively validated in large populations.
  • It is uncertain regarding the NINDS data whether their intention is to present pooled Part 1 and Part 2.  The prior clinical policy used only Part 2 for their NNT calculation, giving rise to an NNT of 8 instead of 6.  It appears they are pooling the data from both parts here.  Either is fine as long as it’s explicitly stated – the primary outcome differed, but the enrollment and eligibility should have been the same.
  • ECASS seems to be missing from their evidentiary table.  The ECASS 3-hour cohort data is available as a secondary analysis.  However, such would probably be Class III data of no real consequence for the recommendation.
  • Level B is probably an acceptable level of recommendation for tPA within the 0-3 hour window.  “Moderate clinical certainty” is reasonable, mostly on the strength of the Class III data.  However, the “systems in place to safely administer the medication” is not clearly addressed in the text.  Most of the published clinical trial and observational evidence involves acute evaluation by stroke neurology.  Does the primary stroke center certification practically replicate the conditions in which patients were enrolled in these trials/registries?  Perhaps this should be split out into a separate recommendation regarding the required setting for safe/timely/accurate administration.
  • Level B is difficult to justify for the 3 to 4.5 hour time window.  There is Class II evidence from ECASS III (downgraded due to potential for bias) demonstrating a small benefit.  The authors then cite Class III trial evidence from IST-3 and ATLANTIS in which no benefit was demonstrated.  Then, they cite the individual patient meta-analysis having similar effect size to ECASS III – because many of the patients in that subgroup come from ECASS III.  Basically, there’s only a single piece of Class II evidence and then inconsistent Class III evidence, which doesn’t meet criteria state for a Level B recommendation (1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).  
  • With both Level B recommendations, the authors also reference “carefully selected” patients, but do not cite evidentiary basis regarding how to select said patients other than listing the enrollment criteria of trials.  If the “careful selection” is strict NINDS or ECASS III criteria, this should be explicitly stated in the recommendation.
  • The Level C recommendations to have shared decision-making with patients and surrogates ought to be obvious standard medical practice, but I suppose it bears repeating given the publications regarding implied consent for tPA.  They mention two publications regarding review and development of such tools, but there is no evidence supporting their efficacy or effectiveness in use.  Frankly, calling them a starting point in such a heterogenous population is along the lines of the broken clock that’s right twice a day.  I would rather say their dependence on group-level data minimizes their practical utility, and clinician expertise will be the best tool for individual patient risk assessment.

Feel free to add your comment and I will incorporate them into my feedback to SAEM.

(Failing to) Identify Severe Sepsis at Triage

This is the holy grail of predictive health informatics in Emergency Medicine – instant identification of serious morbidity, with the theoretical expectation of outcomes improvement due to early intervention.

And, more than almost any condition, accurate early identification of severe sepsis remains elusive.

This is an observational evaluation of the “Australian Triage Scale” in combination with infectious keywords as a tool to identify and manage patients with severe sepsis.  Patients were enrolled at presentation to the Emergency Department, and ultimately followed from triage through their ICU stay – where a clinical diagnosis of severe sepsis was used as the gold standard for outcomes. However, of the 995 patients triaged through the Emergency Department and ultimately diagnosed with severe sepsis, only 534 were identified at triage.  The authors present various diagnostic characteristics for each level of the ATS with regards to acuity, and the AUCs for sensitivity and specificity range from 0.457 to .567 (where 0.5 is basically a coin-flip).  So, the authors’ presented rule-based mechanism is nearly as likely to be incorrect as correct.  I’m not exactly certain how they came to the conclusion “the ATS and its categories is a sensitive and moderately accurate and valid tool”, but I tend to disagree.

These data are consistent with our a priori expectation for these sorts of tools.  The patients who trigger such rules are generally so obviously severe sepsis such rule-based notifications occur after clinician identification, and are simply redundant and alarm fatigue.  Conversely, patients with severe sepsis going undiagnosed upon initial presentation do so because of their atypical nature – and thus tend to fall outside rigid, rule-based constructs.  E.g., computers are not physicians … yet.

“Identification of the severe sepsis patient at triage: a prospective analysis of the Australasian Triage Scale”
http://www.ncbi.nlm.nih.gov/pubmed/25504659

Overstated Benefit of “Compliance” with Massive Transfusion

A couple days ago, @karimbrohi drew a bit of attention to this article on Twitter:

Compliance with Massive Transfusion Protocol improves outcome: http://t.co/Z2yf3EOQeM [Protocol followed- 10% mortality. Not followed – 60%]
— Karim Brohi (@karimbrohi) January 3, 2015

Massive transfusion protocols are, essentially, the standard of care in advanced trauma care.  Coordinated systems to produce timely quantities of appropriate blood products are nothing new.  However, the contemporary usage of MTP has been to describe a protocol with fixed ratio of product – usually approximating a 1:1 ratio of PRBCs and FFP, and some programs include platelets.

This small study retrospectively evaluated the survival of 72 consecutive MTP activations at their trauma facility.  Compliance with 13 quality measures associated with resuscitation and transfusion was 66% overall.  Mortality rates in the cohorts with <60% compliance, 60-80% compliance, and >80% compliance with quality measures were 62%, 50%, and 10%, respectively.  Thus – compliance saves lives!

Maybe?

Tables 4 and 5 compare the baseline characteristics between survivors and non-survivors – and, frankly, it’s hard to decisively say “compliance” made the difference.  Worse initial GCS, median ISS, and AIS head/spine were all significantly associated with poorer outcomes.  Then, as far as differences in “compliance”, there was actually little difference between survivors and non-survivors regarding actual issuing and receipt of blood products.  Rather, the differences were in the quality measures associated with specific lab work – and hypothermia correction, which suffered greatly in non-survivors, almost certainly because they were in the OR for heroic measures rather than in the ICU.  So, it’s rather difficult to reliably state the quality of care was lower for those who did not survive.

And certainly not to account for the entire magnitude of this 60% to 10% mortality advantage!

“Compliance with a massive transfusion protocol (MTP) impacts patient outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25452004

One Troponin is All You Need

The newer, highly-sensitive troponin assays have their pitfalls.  Specifically, specificity.  However, most of the issues associated with diminished specificity are iatrogenic – transitioning from use of troponin as a dichotomous test that used to tell us “yes” to one that does a better job of telling us “no”.

This is a pre-planned substudy as part of a prospective evaluation of patients with chest pain and non-diagnostic ECG, prospectively evaluated for acute coronary syndrome.  These authors looked at hsTnI, but, rather than using the 99th percentile as their cut-off for “negative”, they evaluate the utility of an undetectable hsTnI – which, for this Siemens assay, was <0.006 µg/L.  Based on 1,076 patients evaluated, 647 had an undetectable troponin at initial presentation.  Of these, 4 patients had a subsequently detectable troponin and were adjudicated as acute MI, 3 of which had coronary artery disease and received revascularization.

What was special about those four patients?  Each of them presented within 2 hours of symptom onset.  All told, 399 patients presented more than 2 hours after the onset of symptoms, had an undetectable troponin, and were free of MACE at 7 and 30 days.  These results are generally consistent with other work looking at the sensitivity of the (duh) highly-sensitive troponin assays – capable of conferring an excellent instant rule-out.

So, if you’re asking the question – does this patient have an acute MI? – you’re in good shape.  However, if you’re using highly-sensitive troponin assays, you’ll also need to be smart about appropriately interpreting the indeterminate range – or your patients will ultimately suffer as a result of decreased specificity and downstream over-testing.  Lastly, this is only valid as a diagnostic tool for acute MI – the extent to which it provides prognostic or diagnostic information regarding acute coronary syndromes, coronary artery disease, or ischemic heart disease is still being refined.

“Does undetectable troponin I at presentation using a contemporary sensitive assay rule out myocardial infarction? A cohort study”
http://www.ncbi.nlm.nih.gov/pubmed/25552547

Opiates Are a Gateway Drug … to Opiates

By definition, essentially, all prescription drug abuse starts with a prescription.  Diversion and misuse cannot occur without a physician – well-meaning or not – at the start of the chain.  And, not only are physicians the pipeline for maintaining supply in the community – they’re also one of the sources for minting new abusers.

This simple retrospective study looked at Emergency Department patients receiving treatment for an acutely painful condition.  Patients were then distilled down into those without prior use of opioids within the previous one year – the so called “opioid naive” for the purposes of this classification.  Approximately half of these patients received an opiate prescription at discharge.

Two interesting observations:

  • Those receiving, and filling, a prescription for opiates were far more likely than those who did not receive a prescription – 17% vs. 10% – to fill another prescription for opiates in a 60-day time period one year later.
  • Those receiving, but not filling, a prescription for opiates had only an 8% prevalence of filling another prescription for opiates a year later.

Within the limitations of the selection biases inherent to a such a retrospective evaluation – the message is reasonable: beware the downstream harms of every opiate prescription provided.

“Association of Emergency Department Opioid Initiation With Recurrent Opioid Use”
http://www.ncbi.nlm.nih.gov/pubmed/25534654

Your Lungs Will Not Explode

Gas laws dictate the relationship between pressure and volume.  As pressure decreases, the volume of a gas increases.  If that volume of gas is a pneumothorax … the Aerospace Medical Association and the British Thoracic Society feel such hypobaric conditions, e.g., commercial air travel, are absolutely contraindicated.

But, does the small difference in atmospheric pressure – ~550mmHg versus 760mmHg – truly induce clinically important changes, such as tension physiology?

These clinicians in Salt Lake City enrolled patients with recently-treated traumatic or iatrogenic pneumothorax and subjected them to 2-hours of simulated air travel using a hyperbaric and hypobaric chamber.  Twenty patients were included, 14 of whom received tube thoracostomy for their pneumothorax, with 11 still having residual pneumothorax visible on chest x-ray.  Two types of simulated flights were performed – an initial 554mmHg phase intended to simulate aircraft cabin pressure, and a second phase using 471 mmHg, intended to compensate for the low baseline barometric pressure of 645 mmHg present in Murray, UT.

Did the volume of pneumothoracies increase as atmospheric pressure decreased?  Yes.  Did lungs explode?  No.  Did patients require emergency needle decompression?  No.  Did patients have any change in vital signs?  No.  And, all pneumothoracies returned to their baseline size following return to baseline atmospheric pressure.

Is this durable, generalizable, slam-dunk data regarding prospective guidance for air travel following small pneumothoracies?  No.  But, it’s a lovely bit of dogmalysis demonstrating an unnecessarily absolutist approach certainly is inappropriate, and doesn’t accurately describe the true individualized risks.

“Cleared for takeoff: The effects of hypobaric conditions on traumatic pneumothoraces”

A Happy New EMLitOfNote Year!

Hello, New York City!  You win – with a commanding lead, 4.4% of all visitors to the site, over the past year.  But, after NYC, you have to go down to #5 to get to another U.S. city, and only 4 of the top 10 are ‘merican:

  • New York
  • Sydney
  • Melbourne
  • London
  • Chicago
  • Houston
  • Brisbane
  • Philadelphia
  • Perth
  • Toronto

Australia, I love you too.

What were some of the top posts of the past year?

Pre-Hospital Furosemide – No, No, Also No
It’s almost certainly net harmful for paramedics to give furosemide in the pre-hospital setting.

TMJ Dislocations: A Better Mousetrap?
The syringe technique for relocating mandible dislocations.  Cool.

The Scandal of Dabigatran – A Summary
Unless you’ve been living under a rock, you know we’ve been lied to about Pradaxa.

Azithromycin, the World’s Most Effective Antiviral
What’s more insane than one mostly useless treatment for influenza?  Trying to prove the value in adding an antimicrobial to the mix.

Go Ahead, Age-Adjust the D-Dimer
If you’re going to use D-Dimer to rule-out PE, you probably won’t miss much if you use higher cut-offs in the elderly.

The tPA Cochrane Review Takes Us For Fools
The updated tPA Cochrane Review is just another biased document failing to acknowledge the limitations of the underlying data.

My ACEP tPA Policy Critique
The ACEP Clinical Policy regarding use of tPA was controversial, to put it mildly.

Bayesian Statistics: We’re Dumb as Rocks
How many patients have a disease with prevalence 1/1000, given a test with 5% false positives?  Banana.

Of course, a few great posts from the past couple months simply haven’t had enough of an internet lifetime to accumulate pageviews, including Jerry Hoffman Debates Greg Albers on tPA, the ARISE study, and MR-CLEAN.

Also, a special thanks to Anand Swaminathan, Rory Spiegel, and William Paolo for their guest posts this year.

Thanks for visiting!  I hope you enjoy keeping up and poking holes in the newly published literature as much as I do in 2015!

Helmets Are Good Things

It seems intuitive helmets are beneficial – helmet vs. pavement or brain vs. pavement – yet the topic is somehow controversial.  The only question should not be “if”, but the magnitude of the protective effect.

This brief article is a simple survey of motorcycle and moped accidents in Hawaii, stratified by helmet use or non-use.  There are only small differences in admission to hospital and mortality in the overall cohort, however, those differences are magnified when further broken out into motorcycle or moped use.  The key data: 3.5% fatality rate in helmeted motorcycle crashes versus 8.7% fatality rate in unhelmeted.  The corresponding data for mopeds was 0.7% versus 1.1%.  The authors performed multivariate logistic regression to adjust for age, crash location, and gender with no substantial effect on overall results.

This is retrospective, billing database data, and there are biases and missing information associated with limiting the reporting of only patients for whom EMS was contacted.  This data also does not mention the cause of death – which would make for a much stronger association between fatality and helmet use if head injuries were implicated in the difference.

Regardless, most of the contextual evidence leans towards a protective effect for helmets, and the effect appears magnified as speed increases.  If surviving a motorcycle accident is preferable to the alternative, it seems helmets are the way to go.

“Helmet use among motorcycle and moped riders injured in Hawaii: Final medical dispositions from a linked database”
http://www.ncbi.nlm.nih.gov/pubmed/25494427

Just Poop, It Doesn’t Matter How

Hepatic encephalopathy, a consequence of bacterial overgrowth and impaired ammonia metabolism, contributes to (as these authors say) nearly $2B in healthcare costs due to hospitalization in the United States alone.  Typical, goal-oriented, modern therapy?  Lactulose, a non-digestible sugar, resulting in increased bowel movement frequency.

These authors, appropriately, challenge established dogma – noting, perhaps, there are more effective strategies for clearing the bowels.  As anyone who has undergone colonoscopy is aware, 4 liters of polyethylene glycol solution is the preferred – and highly-effective – bowel-cleansing method.  These authors, therefore, compare standard lactulose therapy with a forced high-volume intake of PEG solution.

With 50 patients randomized in generally similar distribution to either lactulose or PEG, the PEG solution group more rapidly cleared mentation within 24 hours – with 21 of 25 randomized to PEG making at least 1 point improvement on the hepatic encephalopathy scoring algorithm, compared with 13 of 25 in the lactulose cohort.  Victory!  Of course, this sample is too small to truly account for any adverse effects.  8 serious adverse events occurred, include 3 deaths, although the authors feel none were related to the differences between treatment strategies.  And, oddly, diarrhea was noted to be a more frequent adverse event in the PEG group.

Why is this odd?  Because increased frequency of bowel movements is critical to treatment success in HES – and, frankly, if they’re not seeing enough stool output in the lactulose group, they might be doing it wrong.  There’s no specific mention of outputs in the lactulose group, but, ideally, treatment of HES involves a rapid titration of lactulose to adequate stool volume, not a rigid treatment dose.  As such, I might suggest this is a bit of a straw-man comparator between PEG and lactulose, with regard to tests of superiority.

But, I applaud simply thinking outside the box.  Lactulose use has become somewhat dogmatic for the treatment of HES, when, clearly, the answer is just – poop, it doesn’t matter how.

Thanks to Rick Pescatore for forwarding this along.

“Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy”
http://www.ncbi.nlm.nih.gov/pubmed/25243839