Friday, July 3, 2015

What Does EAST Say About ED Thoracotomy?

The resuscitative emergency thoracotomy in trauma – rarely used and rarely successful.  However, for appropriately selected patients in extremis, such timely intervention may be literally life-saving.

The downside: resource utilization associated with saving the neurologically unsalvageable and the risks to providers associated with the procedure.

This is an evidence synthesis performed by a group of authors affiliated with the Eastern Association for the Surgery of Trauma, addressing the topic of patient selection for Emergency Department thoracotomy.  Screening 2,152 studies to review, ultimately, 72, these authors review a total of 10,238 patient encounters in which patients underwent ED thoracotomy.  This results in six recommendations for patients presenting pulseless to the Emergency Department after trauma:
  • In patients with signs of life after penetrating thoracic injury: strongly recommend EDT.
  • In patients without signs of life after penetrating thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients without signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after blunt injury: conditionally recommend EDT.
  • In patients without signs of life after blunt injury: conditionally recommend against EDT.
However, before you start rummaging around in your toolbox for the rib spreaders, it should be recognized the conditional recommendations – except in penetrating thoracic injury – result in absolute intact survival increases only in the range of 20-40 patients per 1000.  Therefore, unless you’re working in a setting of maximal effectiveness and experience, it is unlikely you’ll see even this small absolute benefit.  And, even in the setting with the strong recommendations and excess intact survival benefits of 100 patients per 1000 – your individual hospital system, based on institutional support and experience level of the providers involved, will need to develop specific policies for these situations.  Even though many ED physicians are capable of performing these heroic procedures based on their training, the remaining ED staff and systems in place may not be adequate to support the intervention.

“An evidence-based approach to patient selection for emergency department thoracotomy: A practice management guideline from the Eastern Association for the Surgery of Trauma”

Wednesday, July 1, 2015

New AHA/ASA Endovascular Guidelines

How did I find out about the final publication of the new AHA/ASA Guidelines regarding endovascular intervention in acute ischemic stroke?  I received unsolicited e-mail spam from their representative at a public relations firm, gushing about the technology and offering to put me in touch with their generously available expert.

Before getting into the content, the standard housekeeping exercise regarding declared financial conflicts of interest:
  • Dr. Powers: None
  • Dr. Derdeyn: Microvention, Penumbra, SILK Road, Pulse Therapeutics
  • Dr. Biller: None
  • Dr. Coffey: None
  • Dr. Hoh: None
  • Dr. Jauch: Covidien, Genentech, Penumbra, Stryker
  • Dr. K. Johnston: Roche/Genentech
  • Dr. S. Johnston: None
  • Dr. Khalessi: Covidien, Microvention, Penumbra, Sequent, Codman, Stryker
  • Dr. Kidwell: None
  • Dr. Meschia: None
  • Dr. Ovbiagele: None
  • Dr. Yavagal: Covidien/Medtronic, Penumbra
Yes, Virginia, despite the worldwide availability of methodologists and clinicians to review evidence for guidelines, the AHA/ASA were unable to compose such content absent individuals with professional and financial relationships to the manufacturers of the products involved.  Another sad failure regarding the Institute of Medicine’s Guidelines We Can Trust.

So, what’s wrong with these guidelines?  I’ve written and published multiple times regarding endovascular intervention, and it’s a therapy I’m excited about.  For once, the theory and the practice seem to demonstrably align.  The new stent retrievers seem to substantially benefit patients with viable tissue behind a clot – whether because of collateral circulation, retrograde flow, or semi-permeable occlusion – and have the clot safely removed in a timely fashion.

But, that isn’t everyone.  The most successful trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – were all designed to intervene on a narrow population with salvageable tissue.  The less successful, but still positive, trials – REVASCAT and MR-CLEAN – generally intervened based only on broadly eligible angiographic occlusions.  Such a strategy will definitely catch the few patients with salvageable tissue, but also involves significant resource utilization and procedural risk conferred upon those without the possibility of benefit.

However, that’s what these guidelines suggest – to treat all-comers presenting within six hours, discarding the use of tissue-based criteria for intervention.  The benefit to the corporations involved is obvious, as routine angiography – let alone rapid perfusion calculation – is not widespread.  Without the broadest possible criteria, many centers might not refer patients for intervention.  Given the choice between maximizing yield of this intervention and generating profits for their financial and professional affiliates, the authors of this guideline have chosen the latter.

Not only that, these authors give this recommendation the strongest possible Class I and Level A qualifiers.  The body of the text states this is a result of the findings of the five aforementioned trials published at the time this was drafted.  Unfortunately, from just a simple methodologic standpoint, the authors have developed complete amnesia regarding the entire prior body of negative evidence regarding endovascular intervention – nor acknowledged the open-label nature of these trials stopped early, nor other threats to bias.

So, yet again – from the folks who gave us flawed tPA guidelines and “quality measures” – a guideline we can’t trust.  The Society for Academic Emergency Medicine was solicited to endorse this guideline several months ago, and I was involved in the review process at that time.  Unfortunately, none of the concerns expressed at that time appear to have been addressed – and as such, SAEM is not included among the professional societies endorsing this guideline.

Endovascular therapy is coming.  And, unfortunately, it is certainly going to be coming to many more than for whom appropriate.

“2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment”

Monday, June 29, 2015

The New, Improved, ACEP Clinical Policy for tPA in Stroke

Released with minimal fanfare, approved by the ACEP Board of Directors on June 24th, the revised ACEP Clinical Policy regarding the use of TPA for acute ischemic stroke has gone final.

It is, of course, a vast improvement over the 2012 version – but has, unfortunately, changed for the worse since the draft was posted.

The highlights:

  • The Level A suggestion to consider the risk of ICH with tPA administration has been eliminated.  It has been moved, nonsensically into the Level B recommendations for offering tPA – when, frankly, it’s the only consistent finding across all the evidence.
  • The Level B recommendation in which tPA “may be given” within 3 hours has been strengthened to “should be offered and may be given”.  Obviously, a profound difference.
  • The Level B recommendation for 3-4.5 hours remains unchanged, based on only one flawed piece of Class II evidence (ECASS III), and conflicting Class III evidence (ATLANTIS, IST-3, meta-analyses).
  • The Level C recommendation to engage in shared decision-making now states “when feasible”, which is obviously open to interpretation.
  • No further clarification of “carefully selected patients” or “systems … in place to safely administer the medication” is provided.

Some wins, some losses.  Obviously, the shared decision-making supporting any “offer” of tPA can be very different, depending on an individual clinicians’ interpretation of the evidence – and it is nice to see the prior COI-infested husk of rotten guidelines finally, officially, tossed on the compost heap.  Let us hope (irrationally, of course) the efforts underway in the United Kingdom spur further, independent, investigation with which to better understand and individualize the risks and benefits of treatment with tPA.

“Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department”

Friday, June 26, 2015

It’s the Flu! It’s Not the Flu!

Every year, influenza season travels the globe, led by the four horsemen of the apocalypse, bringing toys and good cheer to obedient little girls and boys.  Unfortunately, this very same influenza contributes to hundreds of thousands of hospitalizations and tens of thousands of deaths in the U.S. alone.  And, despite such ubiquity, clinicians are utterly inept at rapid, accurate diagnosis.

This small study reviews the diagnostic performance of clinicians at a single hospital during the influenza season of 2012-13.  A convenience sample of 270 patients presenting with any history of respiratory or febrile illness were screened and swabbed for influenza, and the results of eventual PCR testing were compared with the sensitivity of the CDC definition of “influenza-like illness” and accuracy of subsequent clinical diagnosis.

The highlights:
  • 42 of 228 patients were positive for influenza.
  • Only 40 out of the entire cohort of 270 met the CDC definition of ILI, a cough or sore throat coupled with fever.
  • 15 of influenza positive patients were thought to have influenza by the treating clinician, as well as 50 of the influenza-negative.
  • A third of actual influenza patients received an antiviral, while half were treated with antibiotics.
Certainly not a paragon of medical prowess.

The authors, unfortunately, use their data as a platform for wickedness.  In the context of inadequate diagnostic skill, the authors call for improved rapid diagnostic tools – such as those manufactured by the study sponsor.  Furthermore, the entire need for such rapid tools is predicated on the assumption of benefit from antiviral therapy – which is also espoused by the authors, who have undeclared ROI with Roche.

“Clinical diagnosis of influenza in the ED”

Wednesday, June 24, 2015

Let’s Reverse: Dabigatran

‘Round EMLoN headquarters, we’re big fans of a few medications.  Oseltamivir.  Ticagrelor.  Alteplase.  And, finally, dabigatran.  After all, a blog needs content – and controversy begets content.  Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional "newly discovered" adverse events.  It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.

This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options.  The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab.  Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab.  By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran.  However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events.  Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.

The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab.  The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable.  Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery.  As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly.  There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.

Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group.  The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues.  In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors.  Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation.  And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.

In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires.  Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies.  The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.

Finally, as a bit of an aside, the accompanying editorial is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors.  Is it really so difficult to identify qualified editorialists without the most egregious possible COI?

“Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy  male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial”

“Idarucizumab for Dabigatran Reversal”

Monday, June 22, 2015

New Text Message: Be a Hero! Go!

This pair of articles from the New England Journal catalogues, happily, the happy endings expected of interventions undertaken to increase early bystander CPR.

The first article simply describes a 21 year review of outcomes in Sweden following out-of-hospital cardiac arrest, measuring by 30-day survival in patients who received bystander CPR prior to EMS arrival, with those who did not.  In this review, 14,869 cases received CPR prior to EMS arrival, with a 30-day survival of 10.5%.  The remaining 15,512 cases did not receive CPR prior to EMS arrival, and survival was 4.0%.  This advantage remained, essentially, after all adjustments.  Thus, as expected, bystander CPR is good.

The second article is the magnificent one, however.  In Stockholm, 5,989 lay volunteers were recruited and trained to perform CPR.  Each of these volunteers also consented to make themselves available by contact on their mobile phone to perform CPR in case of a nearby emergency.  Patients with suspected OHCA were geolocated, along with those enrolled in the study, and randomized into two groups to either contact nearby volunteers, or not.  In the intervention group, 62% received bystander CPR, compared with 48% of the controls.  The magnitude of this difference was statistically significant, but, however, the survival difference of 2.6% (CI -2.1 to 7.8) favoring the intervention was not.

But, I think we can pretty readily agree - if bystander CPR improves survival, and text messages to nearby volunteers improves bystander CPR – it’s a matter of statistical power, not futility of the intervention.  If the cost of recruiting and contacting CPR-capable volunteers is low, it is likely increased neurologically-intact survival is the result.

This a an excellent initiative I hope is copied around the world.

“Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest”

“Mobile-Phone Dispatch of Laypersons for CPR in Out-of-Hospital Cardiac Arrest”

Friday, June 19, 2015

The Era of the Appendectomy is Not Over

However, it might also be accurate to say: The Era of the Emergency Appendectomy is Over.

This is the Appendicitis Acuta trial, a multi-center trial from Finland, randomizing CT-diagnosed, suspected acute appendicitis to either antibiotics or immediate open appendectomy.  Randomizing 530 patents, the trial failed to meet its pre-specified endpoint of non-inferiority, as measured by the outcome of need for appendectomy within 1 year of the initial episode.

And, by “non-inferior”, I’m a little uncertain regarding their clinical interpretation of such.  Their statistical threshold, based on prior evidence, was a non-inferiority margin of 24%, and the actual rate of antibiotic treatment failure was 27%.  However, frankly, I’m not certain how even meeting their non-inferiority margin would be considered clinically acceptable.  I am all for innovating new, cost-effective approaches challenging classical dogma, but uncomplicated laproscopic appendectomies are just about the most-practiced, least harmful of surgical procedures.

The general argument in favor of antibiotics stems firstly from economic considerations – it’s far cheaper to use antibiotics – and secondly from avoidance of operative complications.  Even here, in which patients uncharacteristically underwent open appendectomies, the overall complication rate of 20.5% is inflated by 19 of 273 patients with superficial wound infections.  Minor, transient, treatable complications should not be included in such an analysis.  The 23 patients with continued pain and bowel symptoms at 1-year follow-up, however, is concerning.  But, again, whether such numbers from open appendectomies reflect the long-term symptom rate of laproscopic surgery is questionable.

This trial, at least, does seem to show an antibiotics-first strategy is not unreasonable.  Even as this was a negative trial, 72.7% of patients did avoid recurrent appendicitis and surgery – and of those who did require surgery, only a handful crossed-over on the initial hospitalization.  Additionally, the delay in definitive management was not specifically associated with increased complications.  It would be interesting to someday see 5- and 10-year follow-up, and whether further patients ultimately fail non-operative management, as truly, the lifetime recurrence rate is the better measure of a successful delayed antibiotic strategy.

I would not fault adoption of a strategy of offering antibiotics and observation – but, without better long-term data, I personally would be opting for the appendectomy.

“Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis”

Wednesday, June 17, 2015

Can You Diagnose PE With a Walk Test?

So, no.

You can stop reading now, if that’s enough information to satisfy your curiosity.  There is, however, a little more to it.

These authors describe a prospective evaluation of 114 Emergency Department patients with either suspected or confirmed acute pulmonary embolism.  Patients were enrolled by convenience selection during the hours research assistants were in the ED.  Each enrolled patient underwent a 3-minute walk test while research assistants measured changes in heart rate, respiratory rate, and oxygen saturation.

In short, ambulation induced significant changes in heart rate and oxygen saturation between those who did, and did not, have pulmonary embolism.  A change in heart rate of 10 bpm gave a sensitivity of 97% (95% CI 83 to 99%) and specificity of 31% (95% CI 22-42%), while a drop in O2 saturation of 2% gave a sensitivity of 80% (95% CI 63 to 91%) and specificity of 39% (95% CI 30 to 50%).  Obviously, these test characteristics are poor – excepting, perhaps, a potentially useful negative likelihood ratio, particularly when both variables are utilized.  However, there are also serious issues with their gold-standard for diagnosis of pulmonary embolism – with nearly 30% of their cohort undergoing ventilation/perfusion scans.

I appreciate these authors’ attempt to describe the test characteristics of, essentially, a free, non-invasive physiologic stress – and, even if the current data does not support routine use, it’s probably worth continuing to explore.

“Ambulatory vital signs in the workup of pulmonary embolism using a standardized 3-minute walk test”

Monday, June 15, 2015

Chillin’ Children After OHCA

Once upon a time, many adults suffering an out-of-hospital cardiac arrest received therapeutic hypothermia with a target temperature of 33°C.  Then, along came the Targeted Temeperature Managment trial – in which 36°C seemed to be just as good as 33°C.  Now, just to throw another confounder in the mix, we have a trial comparing 33°C to “therapeutic normothermia” – 36.8°C – and we’re doing it in children to address concerns regarding generalizability from adults.

Very detailed summaries of the numbers, methods, and enrollment can be found on other #FOAMed sites – particularly St. Emlyns and ALiEM.  But, the high points:

  • Many – 1,355 – were screened, but ultimately only 260 were randomized and included in their primary analysis.
  • Adherence to temperature management protocols was good or adequate in ~90% of cases.
  • Hypothermia was implemented for 48 hours, followed by normothermia up to 120 hours total to match the normothermia group.
  • In contrast to adults, the great majority (72%) of this pediatric cohort suffered a respiratory arrest.
The outcome: no statistical difference, with 20% of the hypothermia group alive and functional at 1 year, compared with 12% of the normothermia group, a p-value of 0.14.  Regarding safety, arrhythmias and culture-proven infections favored the normothermia group, 1% vs. 5%, and 39% vs. 46%, but these also did not reach statistical significance.  Finally, both 28-day and 1-year mortality favored hypothermia, with an absolute difference of ~10% in each, but this was not statistically significant, either.

I will let the authors speak for me here:
“One important potential limitation of the trial is that, on the basis of the observed confidence limits for treatment differences, a potentially important clinical benefit cannot be ruled out despite the lack of a significant difference in the primary outcome measure. A larger trial might have detected or rejected a smaller intervention effect. Indeed, there was a significant difference in survival time with therapeutic hypothermia, although this was a secondary outcome measure.”
The relative likelihood of benefit for hypothermia in this trial was 1.54, with a 95% CI of 0.86 to 2.76.  Now, this result crosses 1, and therefore requires interpretation in two contexts.  The first is the normal distribution:

In which we visualize the frequency of potential outcomes, and the important realization the more frequent "true" outcome is most likely to occur near the center of the 95% CI range.

And, the more important context:

In which we interpret these data in the context of prior results, generalized from other settings.  In this case, our prevailing opinion is one in which we suspect hypothermia – with much uncertainty regarding the details – is beneficial.  As you can see, the effects of even “statistically significant” findings have only limited practical impact on the "good bet" or the "long shot".  Hence, the results of this study – which simply barely fail to reject the null hypothesis – do not hardly move the needle against the prevailing opinion.

I tend to side with the authors of this “negative” study: it is mostly likely underpowered to detect the expected benefit, and it is still reasonable to cool children following OHCA.  There are many questions that remain regarding the temperature, duration, and other details – not limited only to children – but it would be erroneous to say this trial refutes the practice of hypothermia in children.

“Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children”

Friday, June 12, 2015

Where’s the Beef With TXA?

CRASH-2 was a massive, international undertaking, testing the utility of tranexamic acid to improve outcomes in bleeding trauma patients.  When given with 3 hours, there were significant reductions in mortality due to bleeding – and the current push for its widespread use was born.

However, this study, and others like it, is not seeing the same magnitude of success as described in CRASH-2.  This single-center, retrospective evaluation of trauma patients reviewed the mortality benefit associated with implementation of a thromboelastography-based TXA protocol.  In 2011, this institution introduced a TEG-based TXA threshold of estimated percent lysis at 30 minutes of >3.0%, and these authors reviewed all cases of trauma patients between 2009 and 2013 meeting that threshold and eligible for treatment within 3 hours.

These authors identified a cohort of 98 patients who met criteria and received TXA, and compared them with a cohort of 934 patients who met criteria and did not.  In-hospital mortality in the cohort receiving TXA was double those who did not (40% vs. 17%), and this disadvantage persisted despite adjustment for age, gender, mechanism, ISS, hypotension, and base excess.  TXA usage was also not associated with resolution of hyperfibrinolysis, as measured by follow-up TEG, but neither was it associated with an increase in thromboembolic events.

Unfortunately, this retrospective evaluation is biased by confounding and unmeasured selection imbalances.  It is, however, not the only study questioning the value of TXA in the setting of routinely well-resuscitated, modern trauma evaluation.  Nothing in this small review provides compelling evidence regarding cessation or tailoring of TXA therapy in bleeding trauma patients, but it does support its continued evaluation for its role in organized, modern trauma settings.

“The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis”