“DAWN” of the Mismatch Era

It wasn’t truly so long ago the treatment for an acute stroke was virtually nonexistent. Then, it progressed, with patients eligible for treatment within 3 hours … then 4.5 hours … then 6 … and, now, 24 hours. Whatever happened to “time is brain”? How can we possibly be treating patients out to a day after onset of symptoms?

This is the DAWN trial, randomizing patients with acute ischemic stroke to endovascular intervention or medical management within 6 or 24 hours of symptom onset. Eligibility criteria included occlusion of the internal carotid or proximal middle cerebral artery paired with one of three different clinical syndrome/infarct core mismatches based on CT or MRI perfusion imaging: three cohorts with NIHSS of 10 or 20, with differing sizes of infarct cores. The underlying theory here stems from observations of the viability of cerebral tissue as dependent upon collateral circulation, rather than simply the linear passage of time.

This is, as you might already have gathered from the press releases, a positive study. Unfortunately, it was so positive it was stopped early for benefit based on a primary outcome these authors almost certainly created uniquely to support early termination of these sorts of trials: the “utility-weighted modified Rankin scale”. Rather than use the traditional mRS as in all other stroke trials, or, even, the statistically flawed “ordinal shift analysis”, these authors assigned point values to the various mRS categories, those with the least disability receiving the most points. This resulted in the potential enrollment of 500 patients being stopped at the earliest possible pre-specified interim analysis with a mere 200 patients enrolled.

Tossing out their nonsensical fake outcome measure for the more easily approachable mRS categories, 52 of 107 (49%) of thrombectomy patients were functionally independent (mRS 0-2) at 90 days versus 13 of 99 (13%) of those in the control group. These results were roughly consistent across their various subgroup analyses, although, with such a small trial, the confidence intervals get awfully wide, awfully quickly. That said, despite all the other associated trial shenanigans, it is fairly obvious this sort of treatment is helpful to patients. I’ve been preaching tissue-based approaches to therapy for a couple years now, and despite this trial’s individual issues, in a Bayesian sense these results are consistent with prior evidence.

Of course, this does not actually indicate the window for screening ought to be 24 hours as will likely be justified from these data – the bounds of eligibility for the study do not simply translate subsequently to clinical policy recommendations. The study design does explicitly stratify patients to 6 to 12 hour and 12 to 24 hour cohorts, but the IQR range for “time from symptom onset” for the entire cohort is 10.2 to 16.3 hours, implying approximately half the 12 to 24 hour cohort was actually randomized between 12 and 16 hours. This leaves a paucity – approximately 25 patients in each arm – of data to inform treatment in the 16 to 24 hour window. Contrariwise, these data also do not explicitly exclude patients beyond 24 hours as potential candidates for intervention, as this is a tissue-based, not time-based, paradigm. Further prospective study will be needed to determine the precise time window at which perfusion screening for large vessel occlusions ultimately becomes so low-yield there is no value in the pursuit.

These authors also do not provide useful information regarding the number of patients screened for possible inclusion. Much will be made of these results, with a likely profound impact on our approach to stroke. To properly design stroke systems of care and project resource utilization, physicians and policy makers need data regarding the clinical characteristics of all patients evaluated and those features best identifying those who ought be triaged or transferred to specialized centers.

Finally, of course, there is the perpetual elephant in the room – heavy involvement from the sponsor in the conduct of the study, along with multiple authors on the payroll. These financial conflicts of interest always threaten internal and external validity by limiting generalizability and amplifying apparent effect sizes. All this said, however, this is probably an important step forward in the evolution in our approach to stroke.

“Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct”
http://www.nejm.org/doi/full/10.1056/NEJMoa1706442

It’s SAH Silly Season Again!

A blustery, relentless wind is blowing the last brittle teeth from the trees here in late November – which must mean it’s time to descend, yet again, into decision-instrument madness. Today’s candidate/culprit:

The Ottawa Subarachnoid Rule, once-derived, now-validated in this most recent publication highlighting their prospective, observational, multi-center follow-up to the original. The components are as you see above, and the cohort eligible for inclusion were neurologically intact “adult patients with nontraumatic headache that had reached maximal intensity within 1 hour of onset”. Over four years, six Canadian hospitals, and a combined annual census of 365,000, these authors identified 1,743 eligible patients with headache, 1,153 of whom consented to study inclusion and follow-up. Of these, there were 67 patients ultimately diagnosed with SAH, and the Rule picked up all of them for a sensitivity of 100% (95% CI 94.6% to 100%) – and a specificity of 13.6% (95 CI 13.1% to 15.8%).

Unfortunately, take the infographic above and burn it, because, frankly, their route to 100% sensitivity is, essentially: everyone needs evaluation.  This can be reasonable when the disease is life-threatening, such as this, but the specificity is so poor in a population with such a low prevalence the rate of evaluation becomes absurd.

If their rule had been followed in this cohort, the rate of investigation would have been 84.3% – or, 972 patients evaluated in order to pick up the 67 positives. Then, in the context of usual practice in this cohort, the investigation rate was 89.0%. That means, over the course of 4 years in these six hospitals, use of this decision instrument would have saved 1 fewer patient from an investigation for SAH every six months. However, the hospitals included for this validation were also the same ones who assisted in the derivation, meaning their practice was likely already based around the rule. I expect, in most settings, this decision instrument will increase the rate of investigation – and do so without substantially improving sensitivity.

Furthermore, their definition also includes patients with a diagnosis of non-aneurysmal SAH who did not undergo intervention, a cohort in whom the diagnosis is of uncertain clinical significance.  If only those with aneurysms and morbidity/mortality-preventing interventions were included, the prevalence of disease would be even lower.  We would then be looking at even fewer true positives  for all this resource expenditure.

The other issue with a rule in which ~85% of patients undergo investigation for headache is the indication creep that may occur when physicians apply the rule outside the inclusion criteria for this study. The prevalence of SAH here is very high compared with the typical ED population presenting with headache. If less strict inclusion criteria are used, the net effect willy likely be to increase low-value investigations in the overall population. Dissemination of this decision instrument and the downstream application to other severe headaches in the ED will likely further degrade the overall appropriateness of care.

Finally, just as a matter of principle, the information graphic is inappropriate because it implies a mandated course of medical practice. No decision instrument should ever promote itself as a replacement for clinical judgment.

“Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache”

http://www.cmaj.ca/content/189/45/E1379.abstract

The Acetaminophen/Ibuprofen Ascendancy

The new hotness of the day is the piece out of JAMA comparing our various oral analgesic treatment options for acute pain the Emergency Department. This relatively mundane line of research has been relatively fertile over the last few years, so, what do we have in store here?

This was a double-blind, placebo-controlled trial of four different analgesic combinations for acute extremity pain. To enter the trial, one of the criteria was receipt of an imaging study, which served twofold: an assumed proxy for more serious injuries and pain, and because it increased ED length-of-stay enough to reduce patients lost to follow-up for their primary outcome. The primary outcome, then, was reduction in pain on a 0 to 10 numerical rating scale at the 2-hour mark, with an interim 1-hour mark recorded as well.

The study drugs were as follows: 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Approximately 100 patients per arm were targeted from their sample size calculations, and they ultimately randomized 416 into generally similar groups with respect to final diagnoses.

The outcomes are essentially a wash – raising a question of whether there is any advantage to opiate therapy for this indication.  In our beautiful public health tapestry of increasing opiate misuse and addiction, any opportunity to reduce opiate prescribing is important.  There are some reasonable takeaways with respect to the relative efficacy of ibuprofen/acetaminophen, oxycodone/acetaminophen,  hydrocodone/acetaminophen and codeine/acetaminophen combinations, but their clinical relevance is highly questionable considering the doses tested in this study.  This is, unfortunately, essentially a straw-man comparison between an adequate dose of non-opiate analgesia compared with the least-adequate preparation of each of the commonly used combination opiate products.  A proper comparison in patients with severe pain ought to use a more typical maximal dose, which would probably be twice as much of each of the combination opiate products.

There are a few other small oddities relating to this study, of course. As an unavoidable consequence of the study setting, 60% of their study cohort identified as Latino and another 31% identified as black. There are potential genetic differences in pharmacokinetics relating to ethnicity, as well as cultural factors relating to the cohort enrolled at the study site, so the generalization of these data requires some caution. The study protocol states patients were to be asked whether they were satisfied with their pain control and side effects were to be recorded (nausea, vomiting, itchiness, etc.), but these are not reported in the final manuscript or supplement. Finally, these data are also limited, essentially, to sprains, fractures, and contusions. This represents an important slice of outpatients seeking analgesia, but may not be applicable to other types of pain.

Overall, however, this is reasonable evidence to support strategies of combination non-opiate therapy in patients without contraindications to both acetaminophen and ibuprofen.  It should not, however, be offered as evidence of the disutility of commonly used combination opiate preparations.

“Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department”

https://jamanetwork.com/journals/jama/article-abstract/2661581

Why Are Children Dizzy?

Vertigo presentations in adults are nearly always benign – with cerebral ischemia generally the most worrisome diagnosis in the differential. But, what about children? With a much lower risk for stroke, but also spared the other decay and decrepitude of aging, ought we be more or less concerned?

The short answer: mostly no. However, the etiologies of pediatric vertigo are almost certainly different.

In this short systematic review comprised of 24 studies and 2,726 children, the vast majority of cases resulted from generally benign etiologies. The most common diagnosis was ascribed to “vestibular migraine”, at about a quarter of the cases, followed by a smattering of peripheral vertigo and labyrinthitis-spectrum disorders. Not until diagnostic prevalence approached ~1% of cases did the most serious underlying etiologies begin to manifest, with central nervous system tumors, demyleninating disease, and ototoxic medication effects at the top of the lists of infrequent findings.

The limitations of this analysis include lack of generalizability to the Emergency Department, as several of the included articles are drawn from outpatient subspecialty case series review. A reasonable takeaway from these data, at least, as in adults, is serious underlying etiologies are very infrequently, and isolated vertigo need not be particularly worrisome absent other important neurologic findings.

“The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases”
https://www.ncbi.nlm.nih.gov/pubmed/29095392

And, The Safest Pediatric Sedation Drug Is …

Ketamine.

This ought not surprise virtually anyone, considering the vast body of experience physicians have performing safe, effective procedural sedation with ketamine. However, medicine is prone to its dogmatic confirmation bias, so I applaud these authors for this important report.

This is a prospective, observational, multi-center cohort specifically evaluating all episodes of procedural sedation for serious adverse events and important interventions. These authors recorded medication cocktails used for sedation, any adjunctive use of medication, the procedure performed, fasting status, and underlying health risks, and then tracked the outcomes of each procedure performed.

Ultimately, they included 6,295 children and sedation events in this study. The most commonly used sedation medications were ketamine, propofol, and combinations of ketamine, propofol, and fentanyl. Serious events were rare, occurring in about 1% of sedations – and, likewise, so were important interventions. Furthermore, the vast majority of events and interventions were simply temporary use of positive pressure ventilation in response to periods of apnea. Importantly, no patients required intubation or unplanned hospital admission. Oxygen desaturation was tracked separately from serious events and, along with vomiting, occurred in approximately 5% of sedation procedures.

With regard to other contributing factors to serious events or interventions, any deviation from ketamine monotherapy increased such risks. Whether it be combining ketamine with another opiate or benzodiazepine, or whether propofol were used alone or in combination, all increased the risk of serious events a small absolute amount over the baseline. Several figures included in the manuscript describe the various risk factors associated with serious outcomes with generally predictable associations, including increased risks with periprocedural opiate use, and decreased vomiting when ketamine were excluded.

Overall, even though the short answer to the question posed in the title is “ketamine”, the slightly longer answer is “any choice is probably fine”. Even though the relative risks are increased, the absolute risks are small – and the severity of interventions required, despite their labeling, were essentially benign.

“Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children”
https://www.ncbi.nlm.nih.gov/pubmed/28828486

The Best Antibiotic Stewardship Money Can Buy

Believe it, or not:

Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.

So, should we all be jumping on the procalcitonin bandwagon? Chances are, you probably already have – check with your critical care team, and I expect you’ll find some implementation of a procalcitonin-based protocol supporting antibiotic stewardship. The underlying concept is hardly unreasonable – when sensitive markers of bacterial infection are low, antibiotics can be discontinued.

However, the evidence base – as helpfully pooled in this individual-patient meta-analysis – is nothing more than a carefully orchestrated disinformation campaign by the manufacturers of these assays. Roche, Thermo-Fisher and bioMérieux have an obvious vested business interest in publishing favorable research findings in support of procalcitonin-based treatment algorithms, and it should come as no surprise the authors have a couple items to declare:

PS, MC-C, and BM have received support from Thermo-Fisher and bioMérieux to attend meetings and fulfilled speaking engagements. BM has served as a consultant for and received research support from Thermo-Fisher. HCB and MB have received research support from Thermo-Fisher for a previous meta-analysis regarding procalcitonin. DWdL’s hospital received financial support for the randomisation tool by ThermoFisher. DS, OB, and MT have received research support from Thermo-Fisher. TW and SS have received lecture fees and research support from Thermo-Fisher. CEL has received lecture fees from Brahms and Merck Sharp & Dohme-Chibret. JC has received consulting and lecture fees from P zer, Brahms, Wyeth, Johnson & Johnson, Nektar-Bayer, and Arpida. MW has received consulting and lectures fees from Merck Sharp & Dohme-Chibret, Janssen Cilag, Gilead, Astellas, Sano , and Thermo-Fisher. FT’s institution received funds from Brahms. CC has received an unrestricted grant of €2000 from Thermo-Fisher Scientific, and non-fiancial support from bioMérieux for the ProToCOLD study. YS has received unrestricted research grants from Thermo-Fisher, bioMérieux, Orion Pharma, and Pfizer. ARF has served on advisory boards for Novavax, Hologic, Gilead, and MedImmune; and has received research funding from AstraZeneca, Sanofi Pasteur, GlaxoSmithKline, and ADMA Biologics. J-USJ declares that he was invited to the European Respiratory Society meeting 2016 by Roche Pharmaceuticals.

And, it’s clearly no coincidence most of the 26 trials included in this systematic review are authored by those same financially-supported authors above – so, it’s turtles all the way down for this meta-analysis.

The results, then, for what they’re worth, despite all the concerted effort to spin them, are rather bland. The mortality differences are zero in the outpatient settings, and small enough in the intensive care unit side to potentially be skewed by design. The only signal I might ascribe reliable in these data is: procalcitonin does reduce antibiotic exposures. This manifests in practice in two different fashions, depending on the setting. In the outpatient setting, where virtually all the antibiotics are unnecessary (one of these trials enrolled patients with “bronchitis”!), it gives the clinicians a crutch to fall back upon to prevent them from practicing bad medicine.  In the intensive care unit, it helps titrate the use of broad-spectrum intravenous antibiotics, which is likely to reduce a number of important downstream effects.  I don’t object to the latter application, but my recommendation for the former: just don’t practice bad medicine in the first place (easier said than done, sadly).

So, the takeaway I’d like to promote in the context of this article – and its simultaneously published Cochrane Review by the same, COI-infested authors – is skepticism regarding the effect sizes for procalcitonin-guided therapy. These data do not exclude its clinical utility for the stated purposes, but its use ought be considered in the narrowest of clinical situations, and probably in those at the highest-risk for harms from otherwise clinically confounded antibiotic exposures.

“Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis”
https://www.ncbi.nlm.nih.gov/pubmed/29037960

Also, if you’re persistent enough to scroll to page 126 in the Cochrane Review full text, you glean this lovely pearl:
Philipp Schuetz received support (paid to his employer) from Thermo Fisher, Roche Diagnostics, Abbott and bioMerieux to attend meetings and fulfil speaking engagements. These conflicts breach Cochrane’s Commercial Sponsorship Policy (Clause 3), therefore Philipp Schuetz will step down as lead author at the next update of the review. Dr Schuetz’s declared conflicts were referred to the Funding Arbiter Panel and Cochrane’s Deputy Editor-in-Chief who have agreed this course of action but as an exception which does not set a precedent for similar situations in the future.

Don’t Dilaudid for Headaches

What’s the most common Emergency Department treatment for “migraine” in U.S. Emergency Departments? If you guessed one of our respected go-to medications – metoclopramide, prochlorperazine, ketorolac, or such ilk – you’re be wrong. It’s friggin’ hydromorphone (Dilaudid). Ask for it by name. It starts with a “D”, and your doctor will know what you’re talking about.

For what it’s worth (hopefully), these data are out of date – coming from the 2010 National Hospital Ambulatory Medical Care Survey in an article published in 2014.  In their report, over half of patients treated for headache in the Emergency Department received opiate therapy, and hydromorphone led the pack. But, if hydromorphone is so widely used, are the rest of us responsible adults missing something?

No.

This is a randomized, double-blind trial in which patients with migraneous headache in the Emergency Department were treated with either hydromorphone or prochlorperazine intravenously. The dose for hydromorphone was 1mg and the prochlorperazine 10mg, with those receiving prochlorperazine concurrently given diphenhydramine 25mg. The primary outcome was headache relief at 2 hours, as measured by patient reported symptoms and by any use of rescue medications, and patients could receive a second dose of the active study medication at the 1 hour mark.

These authors enrolled 127 patients, and at one hour, 15% of the prochlorperazine cohort still had severe or moderate headache, while 48% of the hydromorphone cohort reported the same. Similar absolute magnitudes of patients in the hydromorphone cohort requested a second dose of medication or required use of an off-protocol rescue medication. Then, the study was stopped – they expected to enroll 208, but a pre-planned analysis after 120 required the study be terminated with respect to the observed treatment difference.

And, that’s what I’d suggest be done in this case to hydromorphone use for headache – terminated. I hope the next time a report is published regarding the medications used for acute headache in the Emergency Department, hydromorphone has virtually disappeared from the list.

“Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine”

https://www.ncbi.nlm.nih.gov/pubmed/29046364

The Top “Overuse” of 2016

Another entry in JAMA Internal Medicine’s lovely “Less is More” series, this is a “systematic review” of the previous year’s literature regarding potentially unnecessary care. Living here in the asylum, it seems all our fellow inmates and I are consigned to issuing weather reports from the tempest – but, hey, baby steps.

Their “systematic review” is not particularly rigorous.  It’s basically a literature search, followed by a subjective distillation by author consensus to those considered to be the most potentially impactful – but, regardless, their list is worth reviewing. Without further ado, the highlights of their ten selections:

  • Transesophageal echocardiography is more informative than transthoracic in illuminating the etiology of a stroke, but the additive information does not have a clear downstream benefit on outcomes.
  • Patients undergoing computed tomography to rule out pulmonary embolism without algorithm-compliant use of D-dimer suffer from overuse and low-value testing.
  • CT use increased in all Emergency Department patients with respiratory symptoms, with no evidence of downstream change in prescribing, hospital admission, or mortality.
  • Supplemental oxygen does not demonstrate benefit in patients with chronic obstructive pulmonary disease and mild exertional hypoxia.
  • Small improvements in antibiotic prescribing were seen when comparisons to peers were performed.
  • A shared decision-making implementation for Emergency Department patients with chest pain increased patient engagement and demonstrated a secondary effect of diminished admission and cardiac testing.

Wizard.

“2017 Update on Medical Overuse: A Systematic Review”
https://www.ncbi.nlm.nih.gov/pubmed/28973402

Morphine Not a Good Adjunct For Pediatric Pain

Treating acute musculoskeletal pain in the Emergency Department is a common occurrence – and even on the docket as a time-to-analgesia quality measure. Where we frequently see failures and delays, however, are in children, with much written regarding oligoanalgesia and the dragging of feet before any sort of pain management. Furthermore, adults are frequently managed with opiate therapy, which, despite its various pitfalls, may be considered to stand above the commonly used ibuprofen and acetaminophen monotherapy in children.

So, does it work better to combine an oral non-steroidal analgesic with opiate therapy in children? Or, perhaps, is even an opiate alone better with regard to adverse effects? That is the question asked by this three-arm, double-blinded, placebo-controlled, randomized trial. Children with painful musculoskeletal injuries were randomized either ti 10mg/kg oral ibuprofen, 0.2mg/kg oral morphine, or the combination of both.

The winner is: not children. With 91 analyzed in the ibuprofen-only arm, 188 in the morphine-only arm, and 177 in the combination arm, there were no reliable differences between analgesia between groups. More disappointingly, the average pain score on the visual analogue scale was ~60mm across all groups, and no group improved more than 20mm within an hour. The authors considered a VAS score of <30mm at 60 minutes to represent adequate pain control, and less than a third from each group achieved this. There were no serious adverse events in any group, but 20% of those receiving morphine complained of mild adverse events, mostly nausea and abdominal pain, compared with 7% of the ibuprofen-only arm.

So, still at square one for oral analgesia – but, at least, this negative trial helps inform our avoidance of the intervention tested here.

“Oral Analgesics Utilization for Children With Musculoskeletal Injury (OUCH Trial): An RCT”
http://pediatrics.aappublications.org/content/early/2017/10/09/peds.2017-0186

Alas, Abscesses [heart] Antibiotics

“Fake news!” All you need for effective treatment for abscesses is an incision and drainage procedure – adjunctive antibiotics are just unnecessary exposures with only marginal benefit, at best.

Then, unfortunately, two trials have been published in the New England Journal of Medicine showing benefit for antibiotics – either trimethoprim-sulfamethoxazole or clindamycin – improve the rate of clinical cure. The magnitude of benefit was somewhere in the range of a number needed to treat between 7 and 14, with infrequent harms, suggesting the balance of benefit may favor antibiotics. However, the abscesses included in these study tended to be large, suggesting perhaps these results weren’t easily generalizable.

This is a subgroup analysis of one of these two studies, trying to dredge out a specific population for whom antibiotics weren’t actually of value. And, unfortunately, for the purists among us, the results are bleak. Accounting for the diminishing statistical power and reliability of such an analysis, there are few useful signals within these data. Neither the size of the abscess nor the area of surrounding erythema reliably predicted diminishing returns from adjunctive antibiotics, nor did presence of fever or comorbid illness. The only probably reliable signal in these data, consistent with results in the era prior to MRSA, shows antibiotics are probably unnecessary for those who are not infected with staphylococci. Unfortunately, until that point where the causative agent can be easily ascertained at the time of I&D procedure, these data aren’t terribly useful in a practical sense.

So, the benefit is not universal, but it’s nothing at which to scoff. Perhaps a delayed antibiotic strategy could be considered, but, it seems most patients ought be offered antibiotics following drainage of a clinically significant abscess.

“Subgroup Analysis of Antibiotic Treatment for Skin Abscesses”
http://www.annemergmed.com/article/S0196-0644(17)31383-5/abstract