Friday, April 18, 2014

Pre-Hospital Furosemide – No, No, Also No

In Ottawa, pre-hospital care includes paramedics authorized to treat acute cardiogenic pulmonary edema in the setting of respiratory distress.  Their treatment, sensibly, includes nitroglycerin.  It also, insensibly, includes furosemide.

Decompensated heart failure, resulting in pulmonary edema and dyspnea, is indeed a sort of fluid overload.  However, these patients frequently are not hypervolemic – they may be euvolemic or even hypovolemic, with other underlying etiologies for decompensation than fluid retention.  This pushes the concept of a strategy for the treatment of acute cardiogenic pulmonary edema with furosemide even further down the nonsense pathway.  Yet, there it is.

This study, a retrospective review of presentations with pre-hospital furosemide administration and hospital diagnoses of acute decompensated heart failure, demonstrates essentially nothing.  The primary outcome was designed to detect serious adverse outcomes associated with furosemide administration, but their comparison groups – furosemide given to heart failure, furosemide given to misdiagnosed heart failure, and furosemide not given to heart failure – are clinically heterogeneous and require probably meaningless adjusted comparisons.  The authors find no significant difference, but this is simply a matter of sample size and study design – a treatment given to a group with no chance of benefit obviously suffers only harms.

Most damning, however, is the utter failure of pre-hospital providers to correctly diagnose heart failure.  Of the 272 cases of heart failure diagnosed on arrival to the ED, pre-hospital providers made the diagnosis in only 110 instances.  Then, pre-hospital providers incorrectly diagnosed an additional 58 cases with heart failure and administered furosemide – when the patient was diagnosed with pneumonia, COPD, or another alternative.

Just say no.

“Prehospital use of furosemide for the treatment of heart failure”

Wednesday, April 16, 2014

Go Ahead, Age-Adjust the D-Dimer

If you include D-dimer as part of your practice to exclude pulmonary embolism, you’re probably already aware background levels gradually increase with age.  This results in further deterioration of the already poor specificity.  Happily, this publication in JAMA demonstrates it’s probably safe to gradually increase your cut-off level for D-dimer with age without sacrificing sensitivity.

These authors enrolled 3,324 patients in a cohort with ultimate prevalence for PE of 19.0%.  Of these, 2,898 fell into the “pulmonary embolism unlikely” group and underwent D-dimer testing.  817 met the traditional D-dimer <500 μg/L cut-off and no CTA was performed.  An additional 337 patients met their “age-adjusted cutoff” – "10 x patient age" for those aged greater than 50 years.  Only one patient with a negative D-dimer met their final adjudicated outcome of eventual venous thromboembolism.  The authors, therefore, conclude this strategy of age-adjusted D-dimer cut-off is safe.

However, a handful of patients were lost to follow-up, and the confidence interval for 3-month VTE, considering the sample size, ranges from 0.1-1.7% in their age-adjusted cohort.  Additionally, 7 patients died and 7 patients were evaluated for suspected VTE during the follow-up period.  Only 1 was judged by their 3 experts to have been due to VTE, but this consensus measure for their primary outcome could have profound effects on their ultimate conclusion.  Six different D-dimer assays were also used across their multi-center study, which hinders external generalizability.

But, in the end, it’s probably reasonable.  The harms and costs secondary to testing and treating false-positives and small VTE still likely outweigh any additional misses through this strategy.  Considering this comes from JAMA, it’s likely defensible in the face of peer-review to begin using age-adjusted cut-offs immediately.

“Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism”
https://jama.jamanetwork.com/article.aspx?articleid=1841967

Monday, April 14, 2014

A "Positive" Primary Outcome for PEITHO

Yet, by "positive", as we all too often see, the underlying data comes with a surprise twist.

The Pulmonary Embolism Thrombolysis (PEITHO) trial evaluates single-dose tenecteplase added to conventional heparin therapy for the treatment of “intermediate risk” acute pulmonary embolism.  This includes patients with pulmonary embolism, right ventricular dysfunction on imaging, and elevated cardiac biomarkers.  For the primary endpoint of death or hemodynamic deterioration within 7 days, 2.6% of patients in the immediate thrombolysis group met this outcome vs. 5.6% of patients in the usual treatment arm (OR 0.44, p=0.02).

Unfortunately, this composite outcome obfuscates the difference between treatment arms is limited solely to hemodynamic deterioration.  The downside to thrombolysis – major extracranial bleeding (11.5% by ISTH definition) and hemorrhagic stroke (2.0%) – occurred five times as frequently in the treatment arm.  As a result, the overall 7-day and 30-day mortality were statistically identical.  Ultimately, then, this study paints the treatment decision as a choice between cardiovascular instability and life-threatening bleeding complications.

A couple interesting tidbits from the supplementary appendix:
  • The criteria for myocardial injury was a troponin I >0.06 μg/L or troponin T >0.01 μg/L.  These may be relatively inclusive thresholds.
  • Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.
  • Half the deaths in the placebo arm were “sudden unexplained” or “other”, compared with bleeding or stroke complications in the thromboysis arm.
How does this study fit in with the other recent evidence regarding thrombolysis of non-massive pulmonary embolism, e.g. MOPETT and TOPCOAT?  It means we know there are patients who will benefit – both in short-term hemodynamics and long-term functional status.  However, we're still trying to minimize the number harmed by parsing out the best candidates and choosing the correct dose.  There's a lot of room for disagreement and practice variation during continued investigation, with practice ranging from standard anticoagulation and monitoring to, as Jeff Kline promotes, full-dose thrombolysis with tenecteplase.  At the moment, I fall into the half-dose camp – but always re-evaluating new evidence.

“Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism”

Friday, April 11, 2014

Tamiflu, the Bell Tolls for Thee

Have you read the revised Cochrane Review regarding neuraminidase inhibitors for preventing and treating influenza?  If you have, I’m impressed; it’s 559 pages long.   There are almost 250 pages of outcomes and treatment comparisons.  It is serious business.

And, it needs to be – because these folks from the Cochrane Collaboration are going up against Roche and a spin machine supporting of billions of dollars in revenue and pandemic flu strategic stockpiling.  The question:  do oseltamivir and zanamivir provide symptomatic relief and prevent serious complications from influenza infection with a reasonable safety margin?

Covering 20 oseltamivir (9,623 participants) and 26 zanamivir (14,628 participants) trials under a new data-sharing agreement, these authors ultimately conclude any faith in neuraminidase inhibitors is unwarranted.  Each treatment provided an advantage of less than a day with regard to symptom resolution – reducing the average duration of symptoms from nearly 7 days to slightly over 6 days.  Neither treatment had any effect on hospitalizations.  Pneumonia definitions were not standardized across trials; a 1% relative risk reduction was seen in investigator-reported pneumonia, but no reduction was seen in studies with radiologic objective measures of pneumonia.  Importantly, both neuraminidase inhibitors – osletamivir especially – were associated with adverse effects.  Nausea & vomiting were the most prominent symptoms, but neuropsychiatric disturbances were increased in a dose-dependent fashion.

Even more damning, there was universal risk of bias across trials – particularly for osletamivir.  The quality of the outcome follow-up for post-treatment complications was poor, allocation was not always blinded, and there was evidence of selective reporting of results.  That any government or guideline organization would base massive public health expenditures on a pharmaceutical corporation’s incomplete reporting of low-quality trials is simply indefensible.

So, there is a small, debatably unimportant effect on symptom duration.  There is zero evidence supporting the routine use of these agents to reduce subsequent infection.  This evidence does not exclude an important effect in a selected sub-population, but the authors of this review feel the underlying mechanism of action does not support such use until an effect is verified.  Furthermore, with regard to follow-up trials, the overall incidence of bacterial complications from influenza is low enough a sample size of over 20,000 patients would be required to detect a clinically meaningful difference.

It must be said – there is likewise potential bias on the side of these authors, who have long been vilifying Roche in this battle over open drug data.  The next step, we hope, will be opening the data to all to review and verify their findings.  We can hope, through repeated battles such as this, the open data day will come where we are able to properly protect patients from inadequate trial evidence.

In the meantime – let us purge ourselves of mandates and patient expectations for Tamiflu before the next influenza season rears its ugly head.

“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children”
http://www.bmj.com/content/348/bmj.g2545

Wednesday, April 9, 2014

The Whole Truth, and Anything But

The publication of clinical trials in high-impact journals represents one of the most effective forms of knowledge translation for new medical evidence.  Three of these journals – JAMA, the New England Journal, and the Lancet – perennially rank among the highest-impact.  As I’ve mentioned before, these journals have a higher responsibility to society at large to maintain scientific integrity, as most readers therefore accept the authors presented results and conclusions at face-value.

However, clinical trials are also required to report their results on ClinicalTrials.gov.  These authors review one year’s worth of clinical trials published in the three aforementioned journals and compared the high-impact results with those stashed away on ClinicalTrials.gov.  Of 91 trials identified, 156 primary and co-primary endpoints were identified, but only 132 were described in both sources – and only 61% were concordant between each source.  Of 2,089 secondary endpoints, 619 were described in both sources – and were only 55% concordant.

Furthermore, the authors identified six studies with primary outcomes noted on ClinicalTrials.gov resulting in alternative trial interpretation.  These included changes in disease resolution or progression time, as well as results that achieved statistical significance in publication, but not on ClinicalTrials.gov.

The authors conclude:
“…possible explanations include reporting and typographical errors as well as changes made during the course of the peer review process …. journal space limitations and intentional dissemination of more favorable end points and results in publications."
We ought to expect better vetting of results by journal editors – particularly from sources frequently followed by the lay media.

“Reporting of Results in ClinicalTrials.gov and High-Impact Journals”
http://www.ncbi.nlm.nih.gov/pubmed/24618969

Tuesday, April 8, 2014

A Blog-A-Versary Of Sorts

It’s been three years since I started this blog, during PGY-3 of residency.  If you can imagine, I started out by posting every weekday.

That lasted – looking back – a surprisingly long time.

I’d like to say nowadays is “quality” over of “quantity”, but I’ll let the astute reader judge for themselves.

What have I learned?
  • This is a viable form of academic scholarship that bypasses the bureaucracy and limited format of print journals.  Just a quick look around at the folks who have substantially augmented their careers with an online presence validates this opinion.
  • tPA – we love to hate this drug.  Many of my most-viewed posts concern new trials and publications regarding tPA use in acute stroke.  Other popular topics seem to be cardiovascular & resuscitation topics, along with highly-controversial articles from prominent journals.
  • Blogger and Google Analytics traffic stats still don’t match up, but revisions to Analytics have brought the numbers closer together.
  • As any writer will tell you – the best way to improve your writing is to write.  The best way to improve your critical appraisal is to read other experts – and then throw your own hat in the ring.  Many projects now – including this one – offer the opportunity for intermittent, mentored posts with higher visibility for someone just starting out.
  • Knowledge translation is more important now than ever before.  Creating new knowledge through research is the foundation of advancing the practice of medicine, but the conflicts-of-interest and distortions (sometimes inadvertent) pervading even peer-reviewed publications demand an ever-more-vital skeptical layer of peer review.
  • This current state of online discourse is not the end.  Twitter, blogs, podcasts, Google Hangouts, Global Journal Clubs – don’t forget how “new” these elements are, and watch for (or go create) the next innovation.
Thanks for reading; the pleasure is all mine.

Monday, April 7, 2014

Colloids Will Never Die

People love colloids.  Gross fluid resuscitation with crystalloids makes folks uncomfortable; the general dilutional effects and lack of oncotic pressure associated with crystalloids portends suboptimal volume replacement.

Yet, as we see again, the theoretical advantages of colloids are just that:  theoretical.

In this multi-center study from Europe, ICU patients were randomized – following initial resuscitation – to further resuscitation with crystalloids alone or crystalloids supplemented with albumin to a serum albumin target of 30g/L.  Groups were well-matched at baseline, in medical/surgical comorbidities, organ dysfunction, physiologic parameters, and pre-randomization resuscitation.  This excerpt from the authors’ conclusions condenses the results most simply:
“… the use of albumin in addition to crystalloids to correct hypoalbuminemia, as compared with the use of crystalloids alone, in patients with severe sepsis during their stay in the ICU did not provide a survival benefit at 28 or 90 days, despite improvements in hemodynamic variables.”
The last note is important, and reveals why this study will do nothing to change the use of natural and synthetic colloids for resuscitation:  clinicians love to make numbers look good, and colloids do that better than crystalloids.  Despite increased cost and no ultimate change in the primary outcome of mortality – or any secondary outcome of note – colloids improved hemodynamics in the short term.  Even though colloids are more costly, perhaps there are yet financial advantages to this small, early hemodynamic advantage?  Regardless, we are assured further research on this topic will continue apace.

My wife's contribution to this post:  other important colloids people love include whipped cream, gravy, ketchup, and Jello®.

“Albumin Replacement in Patients with Severe Sepsis or Septic Shock”
http://www.ncbi.nlm.nih.gov/pubmed/24635772

Friday, April 4, 2014

Ignorant About Costs, Interested in Learning

Survey after survey shows: physicians rarely have any idea about the costs of medical care.  And, this is unsurprising – as there is a complex divorce between hospital charges, reimbursements, and ultimate expenses shouldered by patients.  Considering all these variables, it is nigh impossible to clearly communicate the cost of care to an individual in a patient care setting.

But, a ballpark estimate would be nice.

So, how do physicians do with their ballpark estimates of the costs of routine tests and procedures in the Emergency Department?

Using CMS reimbursement rates from 2012 and 2013, this survey of 97 emergency physicians representing 11 EDs in the Salt Lake City area finds they’re usually nowhere close.  Of all the tests and procedures surveyed, only 17% of physician estimates were within ± 25% of the actual CMS reimbursement.  We would be awful on the Price is Right.

Interestingly, the estimates varied widely.  With regards to lab tests and radiology, physicians tended to over-estimate reimbursement by >50%, while under-appreciating the charges associated with CPT codes for administration of IV fluids and IV antibiotics.  I’m not sure how to describe the host of interesting information graphics and tables detailing the bewildering range of inaccuracy, but suffice to say – we could/should/need to do a lot better.

At least, however, physicians self-rated their knowledge of costs of care as low, and over 80% wished they knew more about the charges.  So, hope is not lost – and movements like (the aptly named) Costs of Care ought to receive ready and enthusiastic audience.

“Emergency physician knowledge of reimbursement rates associated with emergency medical care”
http://www.ncbi.nlm.nih.gov/pubmed/24657227

Thursday, April 3, 2014

MAPing Pressor Therapy, a Guide to Nowhere

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Among the many questions in sepsis management, the proper use of vasopressors is one of the most vexing. Despite sparse evidence addressing their overall benefit in the management of septic shock, the use and misuse of vasopressors have been debated ad nauseam. And yet the precise time to begin pressor therapy and the ideal mean arterial pressure (MAP) to target are still very much uncertain.

Authors of the SEPSISPAM trial, or more commonly referred to as “the other sepsis trial published alongside ProCESS", attempt to provide us with some guidance on the ideal MAP goal in septic shock. Pierre et al randomized 776 patients in septic shock, “refractory” to initial fluid bolus (30mL/kg), initiating vasopressor therapy at a MAP goal of either 65 or 85 mm Hg. The pressor used to achieve these MAPs was left to the discretion of the treating physician (though norepinephrine was the first-line pressor in the vast majority of the participating centers).

SEPSISPAM failed to find a difference between a MAP goal of 65 or 85 mm Hg in any of the many endpoints examined, with the exception of the pre-specified subgroup of patients with a history of hypertension. In those randomized to the 65 mm Hg group, they found a small increase in the amount of patients who experienced elevated creatinine levels and underwent renal replacement therapy within the first week of enrollment. Given that there was no difference in 28-day or 90-day mortality or the number of patients who survived to 28-days without organ support, its hard to imagine this momentary ascent into statistical significance as clinically relevant.

More important than the ideal MAP goal for pressor therapy, is how many of these patients should have been started on vasopressors in the first place? Patients were enrolled after they were found to be refractory to initially fluid bolus and then immediately started on pressors. And though the protocol allowed for physician judgment on additional fluid administration after the initial 30cc/kg bolus, if you examine the daily fluid administration during the first 24-hours of resuscitation, very little extra fluid was allotted. Though these patients received approximately 10 liters over the first 5 days of their resuscitation, only 3 liters were given within the first 24 hours. When compared to the ProCESS cohort, who received approximately 5 liters (depending on group allocation) within the first 6 hours, this resuscitation effort is entirely underwhelming.

It is impossible to make definitive conclusions when comparing outcomes from different trials, but these two cohorts appear fairly similar at the time of enrollment. In fact, the ProCESS cohort may have been slightly sicker (lower MAP, higher HR, higher initial blood lactate levels). These two very similar cohorts with almost identical pre-enrollment fluid administration demonstrated two very different resuscitative strategies.  The patients in the SEPSISPAM trial were given very little additional fluid after the initial bolus and were all immediately started on pressor therapy. Conversely, the ProCESS cohort were bolused generous amounts of additional fluid and only half were started on pressors within the first 6-hours of enrollment. The 28-day mortality in the SEPSISPAM cohort was 34% and 36.6% respectively. In contrast, the the ProCESS cohort found a 60-day mortality of 21.0%, 18.2% and 18.9% in the three resuscitative strategies.  Obviously not definitive data but a strong argument against the "Fear the Fluids" campaign that is so rampant in current ED and ICU management of septic shock.

"High versus Low Blood-Pressure Target in Patients with Septic Shock" http://www.nejm.org/doi/full/10.1056/NEJMoa1312173

Wednesday, April 2, 2014

The Troponin to End All Troponins

Yet again, the internet has exploded with magical thinking: “Simple test could help rule out heart attacks in the ER: study

What is this one “weird” trick that builds muscle, saves electricity, gives you a flat belly, and detects heart attacks in the Emergency Department?

It’s just another high-sensitivity troponin publication.

This is a two-year retrospective evaluation of patients presenting to two Emergency Departments in Sweden, culling the electronic health record for patients aged greater than 25 who were evaluated for chest pain and had at least one hs-cTnT level measured.  These patients were then followed through the central Swedish Health Registry for subsequent hospital admissions or death for 30, 180, and 365 days following their Emergency Department Visit.

Of this cohort, 8,883 had an initial hs-TnT <5 ng/L; within 30 days, 15 of these patients received the diagnosis of MI and two patients died.  Thus, a negative initial hs-TnT was associated with a 0.17% absolute risk for MI and a 0.023% risk of death from cardiovascular causes within 30 days.  Therefore, this test is magic.

Except, it isn’t.  We’ve known for almost two decades that negative biomarkers confer an excellent 30-day prognosis.  This is simply a more sensitive version of those prior assays, with the potential to pick up troponin elevations earlier in the time course of cardiac ischemia.  Earlier detection of cardiac ischemia then potentially enables a one-set rule-out, rather than a two-set or three-set traditional evaluation.

However, as is the natural order of things, when the balance of a test shifts to assign greater significance to a negative test result, the significance of a positive test results declines.  Patients admitted to the hospital with hs-TnT levels >14 ng/L received a diagnosis of MI only 30% of the time.  Their data tables are insufficient to estimate the specificity of the test at the cut-offs provided in the paper, but, clearly it is poor.

The authors promote this test as a tool to discharge greater numbers of patients from the Emergency Department.  However, any potential performance improvement will depend on the baseline admit rate at your institution.  Then, ultimately, we’ll need a more sophisticated approach to interpreting this test – moving beyond the dichotomous interpretation of “positive” and “negative” biomarkers, and describe the detectable levels on a continuum in the context of the concomitant disease processes – including, but not limited to, acute coronary syndrome.

“Undetectable High Sensitivity Cardiac Troponin T Level in the Emergency Department and Risk of Myocardial Infarction”
https://content.onlinejacc.org/article.aspx?articleID=1854323