Month: March 2018

Who Still Acutely Uses Fecal Occult Blood Tests?

If you trained or practiced in the last few decades, there’s no doubt you’ve performed hundreds, if not thousands, if not tens of thousands, of fecal occult blood tests. For many years, this has been part of some routine evaluations for suspected gastrointestinal bleeding or anemia without another adequately identified source.

However, this test is pointless, as these folks at Parkland succinctly illustrate. In evaluating the value of the FOBT in the acute clinical setting, they observe two features obviating its utility. First, they argue the test characteristics are utterly inadequate – there are confounders contributing to both false negatives and false positives, leading to either delays or inappropriate interventions. Then, they ultimately note ultimate clinical course depends on the the other presenting features rather than the result of the FOBT.

Specifically, Parkland went from nearly 8,000 FOBT (mostly in the Emergency Department) to zero.

You can too.

“Eliminating in-Hospital Fecal Occult Blood Testing: Our Experience with Disinvestment”

https://www.sciencedirect.com/science/article/pii/S0002934318302195

Metronidazole is Out for C. Diff

Time to update USMLE, ABEM, ABIM, and every other standardized test given in medicine – the old standby, metronidazole, has been downgraded for the treatment of Clostridium difficile infection.

This update from the Infectious Disease Society of America, published last month, refreshes clinical practice guidelines for C. diff. The article covers a few different topics, including the population to be tested, the criteria for diagnosis, and a whole host of management and prevention factors. As with any comprehensive guideline, there is the occasional discordance between the strength of the recommendation and the quality of the underlying evidence, so the generalizability of their recommendations may have limitations.

However, tucked into all the various nuances (which are all mostly worth looking over, of course), is one of the most profound changes – metronidazole has been demoted from first-line for C. diff infection. The co-first line agents are now oral vancomycin or oral fidaxomicin. The authors effectively cite the continued use of metronidazole as anachronistic dogma, with vancomycin repeatedly demonstrated as having greater effectiveness. Cure rates with oral vancomycin range from 80-97%, while metronidazole is a rung down at 70-84%. Unfortunately, the cost of oral vancomycin and fidaxomicin remains highly burdensome – leaving a role for metronidazole, but not preferred as before.

It should be noted virtually every author of the guideline has some sort of relationship with a pharmaceutical company, including the manufacturer of fidaxomicin.  That said, oral vancomycin is generic – if still expensive – and has been around a long time.

“Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)”
http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_By_Organ_System-81567/Gastrointestinal/Clostridium_difficile/

More “Time Is (Not) Brain” Nuances

This article is conceptually quite strange – and that’s evident right in the title. Time from imaging, not time from onset, is the determining factor in outcomes from acute stroke? However, despite the overall oddity of their premise, there’s at least one pearl demonstrated here: patients with excellent collateral circulation are far more resilient.

This is a small, retrospective evaluation of patients undergoing endovascular intervention for large vessel occlusion within 18 hours, dichotomized between those with a “target” and a “malignant” mismatch profile on CT perfusion imaging. The “target” profile has a Tmax>10s volume ≤100 mL, while the “malignant” profile was ≥100 mL.

There were only 154 patients for analysis, only 48 of whom had “malignant” profile – and, in their tiny sample, they observed no association between time from CT to reperfusion and functional outcomes in those with “target” profile, while there was an apparent association between time delays and outcomes for the “malignant” profile. Whether this risk for poor outcomes can be truly assigned to these time delays or other features intrinsic to at-risk tissue, it does, again, demonstrate the marked heterogeneity in stroke patients with regard to their underlying tissue viability.

The value in endovascular intervention drops precipitously when, despite otherwise being eligible, the collateral circulation is insufficient. The “time is brain” absolutism continues to weaken, affecting both those traditionally considered appropriate and those in extended time windows.

“Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke”

http://stroke.ahajournals.org/content/early/2018/03/15/STROKEAHA.117.018858

How Many 6-to-24 Hour Stroke Patients Are Eligible?

So, DAWN and DEFUSE-3 show it is reasonable to use tissue-based criteria to guide intervention, rather than the quaint, but anachronistic, concept of “time is brain.” However, in expanding this window, what is the yield of screening? How many CT cerebral angiograms with specialized perfusion imaging will need to be performed to identify a patient for intervention?

This single-center report 2014 through 2017 at a DAWN trial-participating center found:

  • 2,667 patients with acute ischemic stroke.
  • 792 arrived between 6 and 24 hours of last known to be normal.
  • 298 of those were NIHSS ≥10.
  • 155 of those had proximal anterior large vessel occlusion.
  • 45 of those were non-disabled at baseline and met clinical and imaging mismatch criteria.

The authors also did an analysis for DEFUSE-3 eligibility, and ended up with similar numbers, although there were 15 DAWN-eligible patients who did not meet DEFUSE-3 criteria and 28 DEFUSE-3 patients who did not meet DAWN criteria, so there’s some fuzziness at the bottom of the pyramid, in addition to the limitations of their retrospective review.

So, effectively, a little more than a third of patients presenting between 6 and 24 hours probably meet criteria for screening for large-vessel occlusion, with about half of those identifying an occlusion, and then another third of those having imaging findings with sufficient viable tissue for intervention.

There are almost certainly opportunities to use clinical evaluation – not just a NIHSS cut-off – to improve yield, but there will inevitably be a balance between sensitivity and specificity with respect to resource utilization.

“Eligibility for Endovascular Trial Enrollment in the 6- to 24-Hour Time Window”
http://stroke.ahajournals.org/content/early/2018/03/15/STROKEAHA.117.020273

All Sepsis Is Not the Same

This is a fairly dense informatics evaluation of sepsis, but it boils down to a general hypothesis with some face validity: all sepsis is not the same! This is abundantly obvious from the various clinical manifestations of response to infection, with a spectrum ranging from Group A Streptococcal pharyngitis to gram-negative bacteremia and distributive shock.

This analysis uses genetic expression sampling from whole blood to perform unsupervised machine learning analyses and clustering, and they identify three subtypes the authors term “Inflammopathic, Adaptive, and Coagulopathic”. Whether these are terribly illustrative of the underlying pathology is unclear, but, if you want to be in one of these clusters, you want to be in “Adaptive” with its 8.1% mortality – compared to 29.8% in Inflammopathic and 25.4% in Coagulopathic.

Validity of this specific analysis aside, it’s an interesting example of what may ultimately be a useful approach to treating sepsis – targeting the specific underlying genetic expressions associated with dysregulated immune response or underlying end-organ dysfunction. The best thing about this paper, however, are the acronyms reported for some of the statistical methods: “COmbined Mapping of Multiple clUsteriNg ALgorithms” or COMMUNUAL, and “COmbat CO-Normalization Using conTrols” or COCONUT.

“Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters”
https://www.ncbi.nlm.nih.gov/pubmed/29537985

Yet More Love for the Alvarado Score?

The Alvarado Score for appendicitis has been around a long time – 1986, to be precise. Initially proposed to help with the diagnosis of appendicitis prior to advanced imaging, in a different surgical and observation culture, it has effectively been replaced in cost-effectiveness and timeliness by CT. These authors, however, want to resurrect it in the face of increasing CT overuse.

These authors perform a simple retrospective review of CTs performed at their single institution evaluating patients for abdominal pain, and then retrospectively calculated Alvarado scores from medical record review. Methods are incompletely described, but, effectively, they found about 20% of their 492 cases were Alvarado score ≥9 – and all had appendicitis – or Alvarado score ≤2 – and nearly all were absent appendicitis – and suggest any patients with scores at those extremes should not receive imaging, thus reducing ED length-of-stay and radiation exposure.

It should probably say something that a clinical tool has been around over 30 years without truly gaining traction. I don’t think their proposal is unreasonable – whether using Alvarado or gestalt – to consult prior to imaging for cases with high clinical likelihood, or to discharge with return instructions for cases that are inconsistent with the diagnosis. Cultural factors need to change on both ends of the spectrum, however, to support imaging reduction practice change. Finally, despite the commanding nature of their article title, this is hardly the level of evidence or statistical power to truly describe the safety or effectiveness of this strategy – there are more patients here than in many prospective studies, but this does not replace a well-designed trial, or even some sort of pre-/post-intervention report.

Also: “This study was presented at the 75th meeting of the American Association for the Surgery of Trauma, September 14-17th, 2016 in Waikoloa, Hawaii.” Ah, nice.

“The Alvarado Score Should Be Used To Reduce Emergency Department Length of Stay and Radiation Exposure in Select Patients with Abdominal Pain”

https://www.ncbi.nlm.nih.gov/pubmed/29521805

Useful Pregnancy-Related Guidance

So, I might be alone here, but in my canvassing the interesting literature this morning, I stumbled across this Clinical Expert Series in Obstetrics & Gynecology and thought: “This is great! I wish we’d (myself and my wife) had this four years ago!”

It’s a concise summary of the evidence (mostly lack thereof) and recommendations for things pregnant women “should and should not routinely do during pregnancy.” There’s so much nonsense floating around on the internet, and so many dark wombat burrows full of sinister imaginings, I almost feel this would be a good document to hand out to pregnant patients with adequate levels of health literacy.

A few highlights:

  • Prenatal vitamins are unlikely to be harmful, but potentially unnecessary for women already consuming balanced diets.
  • Alcohol consumption up to 7-9 drinks per week does not appear to be harmful, but no specific threshold for safety is known.
  • Up to 300 mg/d of caffeine is probably safe.
  • Examples of good fish are anchovies, Atlantic herring, Atlantic mackerel, mussels, oysters, wild salmon, sardines, snapper, and trout.
  • Appropriately prepared sushi is unlikely to give you a tapeworm.
  • “Pregnant women should avoid foods that are being recalled for possible Listeria contamination.”
  • Using toxic insect repellent is probably safer than the risk of insect-borne illness, where appropriate.

… and many more!  Useful!

“Dos and Don’ts in Pregnancy – Truths and Myths”
https://www.ncbi.nlm.nih.gov/pubmed/29528917

Wake Up And Smell the Isopropyl

Why? It’s just as good or better than the sweet, sweet taste of ondansetron dissolving under your tongue.

This is a rather small, but quite interesting trial, building upon prior work evaluating the use of inhaled isopropyl alcohol for nausea. It’s better than saline placebo, yes, but what about those actual doctor-type medicines we use so can bill as a Level 3 or Level 4 visit?

This three-arm trial randomized 40 patients each into inhaled isopropyl + ondansetron oral dissolving tablet, inhaled isopropyl + oral placebo, and inhaled placebo + ondansetron oral dissolving tablet. Even despite the limitations of sample size with regard to statistical significance, the isopropyl arms are the clear winners with regard to their primary outcome of nausea score reduction at 30 minutes. Objective outcome measures were mixed – receipt of rescue antiemetics mirrored the primary outcome, but measures of ED length-of-stay and admission disposition could not demonstrate a difference.

Some fun tidbits here – patients were allowed to have an unlimited supply of alcohol medication pads to use throughout their ED stay, not just on initial arrival. They did not quantify how many pads were utilized by patients included in these arms. The authors also evaluated the effectiveness of blinding on their study, and, as expected, found it’s hard to miss the distinctive scent of isopropyl alcohol – and this introduces a potential source of bias to these results.

Overall, at least, it certainly seems reasonable to use isopropyl alcohol pads as adjunctive therapy for nausea in the ED – and as an inexpensive, over-the-counter option for patients (well, and doctors) at home.

“Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial”
https://www.ncbi.nlm.nih.gov/pubmed/29463461

A Non-Non-Answer in Airway Management in OHCA

In a lovely demonstration of the statistical inanity of non-inferiority trials, these authors present a simultaneously insightful and illogical data set examining airway management strategies during CPR in out-of-hospital arrest.

This is a clinical trial from France, randomizing patients out cardiac arrest to either bag-valve mask ventilation or placement of an advanced airway during CPR. Patients with significant challenges associated with BVM could cross over to ETI, and if patients achieved return of spontaneous circulation at any time, they were subsequently intubated as well. All emergency response and airway management was supervised by an emergency physician. Groups were fairly well matched by their randomization by center, and about 10% of the cohort crossed over to ETI from BVM due to failure of ventilation or gastric regurgitation.

Without wallowing too much in the statistical underpinnings, these authors defined a 1% absolute difference in favorable neurologic outcome at 30 days as their primary outcome measure for non-inferiority. Then, if non-inferiority was unable demonstrated, a test of difference would be performed for inferiority.

And, so, after all this, CPC 1-2 survival was: 4.2% in the BVM group and 4.3% in the ETI group, for a difference of 0.11% (1-sided 97.5% CI, −1.64% to infinity). It should be abundantly obvious that – considering the obviousness of their result and its gross failure to meet their statistical threshold – their sample size is completely inadequate. It then unsurprisingly follows their test of difference does not demonstrate inferiority of BMV as compared to ETI.

So, yes, BMV is not inferior, but not non-inferior, to ETI. This is why everyone hates Journal Club.

In the bigger picture, these data generally support deferring advanced airway placement during CPR. These authors did not observe any differences in low-flow time, even in their ETI group – but I would expect this might be a “best case scenario” with respect to minimal interruption and successful airway management.  Considering they have an EP assisting in the resuscitation and airway management, I would probably expect other settings are more prone to airway management failure and interruptions – and, really, the onus should be on those doing more to find solid data to back up their prehospital intervention.

“Effect of Bag-Mask Ventilation vs Endotracheal Intubation During Cardiopulmonary Resuscitation on Neurological Outcome After Out-of-Hospital Cardiorespiratory Arrest A Randomized Clinical Trial”
https://jamanetwork.com/journals/jama/article-abstract/2673550