Ryan Radecki

The Penicillin Allergy Lie

This is a short follow-up study that touches upon a ubiquitous subject of which we’re mostly familiar – most patients with a stated allergy to penicillin do not actually have a true, IgE-mediated reaction. In the original study, these authors performed a standard 3-tier allergy testing on 100 patients with “low-risk” reported allergy symptoms, all of whom tested negative and ultimately passed a 500mg amoxicillin challenge dose. Now, in this study, these authors re-contacted the patients and the primary care physicians to determine the downstream communication, effects of the allergy testing notification, and any adverse events related to prescribing after removal of the allergy from the patient’s chart.

Without going into much detail, there was a huge disconnect – most parents reported relaying the information, most physicians reported no information was relayed, and about half the patients had the allergy still listed in their chart. Regardless, 26 patients filled at least one prescription for a pencillin-derivative medication within the year, and one child developed a rash attributed to the amoxicillin.

The authors use this narrow experience to estimate cost savings attributed to using penicillin derivatives versus cephalosporins or clindamycin, and determine their allergy testing resulted in $1,368.13 in savings. Across the 6,700 reported penicillin allergies annually in their ED, they estimate accurate allergy information and delabeling could save nearly $200k each year.

This hardly represents all the benefits of delabeling, as the antibiotics avoided are also typically broader-spectrum, with greater contributions to antibiotic resistance. Clearly, a simpler, accepted pathway to expedite penicillin allergy delabeling would be of great value.

“Antibiotic Use After Removal of Penicillin Allergy Label”

http://pediatrics.aappublications.org/content/early/2018/04/18/peds.2017-3466

Don’t Give NEXUS II Much Thought For Kids

Into the the world of PECARN, CHALICE, and CATCH, we add NEXUS II. Why? Good question.

This is a planned secondary analysis of the NEXUS Head CT decision instrument among enrolled patients less than 18 years of age. Like most decision instruments, this rule classifies patients into “high risk” or “low risk”, with “low risk” being free of any mandated imaging. Their rule, which I will not recount, was tested in 1,018 blunt head trauma patients, and their rule picked up all 27 of those who required neurosurgical intervention. Unfortunately, it also only classified 330 patients as “low-risk” – for an abysmal 33% specificity.

The authors state it may yet have value, despite this poor specificity, as a one-way decision rule. Unfortunately, one-way decision rules are fraught with peril, as the inability to classify a patient as “low risk” is difficult to ignore. This leads clinicians to ultimately use the one-way instrument as a two-way, despite the bleak positive predictive value. This rule also missed one of 49 patients with “significant intracranial injuries”, meaning it is reasonable to expect it may not actually be 100% sensitive. Considering clinical judgement is vastly superior to this product, and there are enough alternative options, it is reasonable not to give this product another thought.

“Validation of the Pediatric NEXUS II Head CT Decision Instrument for Selective Imaging of Pediatric Patients with Blunt Head Trauma”
https://www.ncbi.nlm.nih.gov/pubmed/29665151

Slow Ketamine is Less Bad than Fast Ketamine

In today’s report of study findings that ought not surprise anyone – slow infusion of ketamine is less bothersome than IV push dosing.

This is a quite small study, randomizing just 62 patients to 0.3mg/kg of ketamine by either IVP over 1 minute, or dilution into 100mL of saline and infused over 15 minutes. Of the 59 completing the study, nearly all patients experience some side effect – 86% of the IVP arm and 70% of those receiving infusion. When qualified by “moderate or greater” side effects, the difference was magnified to be 76% vs. 43%, mostly driven by feelings of unreality or hallucinations. The study was underpowered to detect differences in pain scores, but no underlying difference is suggested by these data.

Ketamine has become increasingly popular for pain control as of late, and these findings help support practice in terms of improving tolerability.

“Slow infusion of low-dose ketamine reduces bothersome side effects compared to IV push: a double-blind, double dummy, randomized controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/29645317

Less is More, Cellulitis Edition

Generally speaking, the diagnosis of cellulitis is a fairly straightforward clinical evaluation – even in the Emergency Department. This article, however, says “we’re doing it wrong!” to the tune of $225M of waste on the inpatient side.

These authors retrospectively reviewed 183 patients admitted through their hospital system for a diagnosis of cellulitis, with a focus on imaging and blood cultures obtained. Of these, 83 (45%) underwent at least one form of imaging, with a handful a greater number, with 8 identifying an important additional or alternative diagnosis. Then, 60 (33%) received blood cultures, one of whom had conclusive culture growth – although the authors do not characterize whether it changed or narrowed antibiotic therapy. They ultimately conclude, in these otherwise non-toxic patients, these tests are of low value and ought be severely curtailed.

As much as I generally agree with the various Less is More-themed articles in this vein, I’m not sure this one entirely hits the mark. These 183 patients are inpatient hospitalizations, with progressive disease or significant comorbid disease – a far cry from the uncomplicated cellulitis representing the majority of our throughput. While these statistics may look grim, and they absolutely reflect generally low-value practice, this is a heterogenous cohort of patients in whom some of these tests were reasonable based on clinical examination and a reasonable pretest likelihood of a clinical important alternative entity. There is prudence and value to be found in reflecting on the assessment of cellulitis – but $225M might be a little bit of hyperbole.

“Clinical Usefulness of Imaging and Blood Cultures in Cellulitis Evaluation”

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2676998

A Validation of YEARS?

A couple of years (ha ha!) ago, the results of the YEARS study were unveiled, a culmination of various ideas towards incorporating pretest probability into the use of the D-dimer for “ruling out” pulmonary embolism. The ideas were not unique to this research group in the Netherlands, but the implementation was – and many awaited some independent confirmation of their results.

This is a step towards that independent confirmation, a multi-center observational evaluation of the YEARS protocol. In this study, these authors collected the data necessary to determine the workup and outcomes via YEARS, but clinical practice was left unchanged. This is of particular importance because, unfortunately, this leaves a glaring hole in their enrollment criteria – YEARS did not have any carve outs for patients in whom D-dimer was not part of the evaluation for PE, whereas in these EDs, patients with high pretest likelihood typically went straight to imaging without D-dimers.

Overall, then, in these 17 Emergency Departments, 1,789 low- and intermediate-risk patients were evaluated for PE, with an overall prevalence of 4%. There were 7 (0.3%) patients determined to have potentially missed PE by three month chart review and follow-up phone calls, with a default assignment of “no PE” for the handful lost to follow-up. In their sample, usual practice led 45% undergoing CTPA and 9% undergoing V/Q. With YEARS criteria implemented, the imaging rate would have been 33% – at the cost of an additional 6 missed PEs. This miss rate, however, is still below the threshold of testing equipoise, balancing the morbidity of anticoagulation versus the morbidity of missing PE.

This is a helpful piece of evidence in support of YEARS, even if it leaves major questions unanswered regarding its use in high-pretest probability patients, to say the least. The imaging reduction estimation, as well, should be considered to be overstated by an observational trial, as the adoption of apparently aggressive new protocols would likely be slower than this theoretical maximum.

One small step forward.

“Multicenter Evaluation of the YEARS Criteria in Emergency Department Patients Evaluated for Pulmonary Embolism”
https://www.ncbi.nlm.nih.gov/pubmed/29603819

Nothing Excludes Pulmonary Embolism?

It’s hard to find a diagnostic pathway with greater variation than that of pulmonary embolism. On one hand, you have the YEARS protocol, in which D-dimer is the definitive gatekeeper without carve-outs or exclusions. On the other hand, you have an article like this – saying even CT pulmonary angiograms are inadequate to rule-out PE.

These authors re-analyzed the data from a previous prospective study enrolling 7,940 patients across 12 Emergency Departments. In this analysis, these authors focused in on the 257 patients for whom a “High risk” Wells score was assigned. Of these, 201 underwent reliable CTPA, 71 of which were read as positive and 130 of which were read as negative. Within 45 days, using chart review and telephone follow-up, the authors determined 16 of these patients were ultimately diagnosed with PE. They conclude the CTPA missed these diagnoses at the index visit, and should not be considered adequate for rule-out in a high-risk patient. They go on to cite the inadequate sensitivity of CTPA as demonstrated in PIOPED-II as justification for their stance.

Unfortunately, there’s not nearly enough information presented here to fully evaluate their findings. The authors are attempting to refute the utility of CTPA as a reliable mechanism for rule-out, but, despite such a small sample, no individual scan follow-up was attempted to overread the initial CT. Then, patients with high Wells scores are obviously at high risk for VTE; it almost certainly reasonable some of these downstream PE are independent events, a possibility towards which the authors are fairly dismissive. The authors report many of these patients were positive for DVT, making a subsequent PE as an independent event even more likely. The PIOPED-II study, landmark or not, was conducted in a comparatively medieval era of CTPA, and those sensitivity findings should not impact current data interpretation. Finally, the CTPA is famous not so much for false negatives as it is false positives. The authors do not account for the possibility some of these downstream diagnoses are false positives, and no characterization of the subsequent diagnoses are given – an important consideration in this era of over-diagnosis of subsegmental PE of uncertain clinical significance.

I certainly do not believe these data should change practice or our opinion of the CTPA as a reliable rule-out for a clinically important PE. More robust, prospective study is necessary to confirm the veracity of their conclusion of these false negatives.

“Ruling out Pulmonary Embolism in Patients with High Pretest Probability”

https://escholarship.org/uc/item/74h4h8qb

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