New Anti-Flu, Just Like the Old Anti-Flu

Mitigating the harm of influenza pandemic is certainly an important endeavor. Despite the clinical importance, however, we’ve simply been kicking the oseltamivir can down the road for over a decade. Given the ongoing controversy over its usefulness, this is suboptimal – and winter, of course, is coming.

The newest agent to the scene is baloxavir marboxil, being developed in Japan. Baloxavir is a selective inhibitor of influenza endonuclease, rather than a neuraminidase inhibitor like oseltamivir. This recent article details the phase 2 dose-ranging study and subsequent phase 3 placebo and oseltamivir-controlled trial, CAPSTONE-1.

There were 1,436 patients enrolled in CAPSTONE-1, 1,064 of whom were ultimately confirmed to have influenza A or B. Most of the patients (~85%) had influenza A. The results are – well, “favorable”, by which I mean most likely “profitable”. Symptom duration in the infected population was attenuated by the the same length of time as oseltamivir, which in turn was about a day shorter than placebo. Various measures of viral expression were improved by baloxavir, which seemed to virtually eliminate detectable infective activity within the first 24 hours. There were a small number of extra treatment-related adverse events in the baloxavir cohort, but there were only a handful in each cohort overall, and it remains to be seen in further surveillance the true incidence.

As anyone who has been afflicted by influenza can tell you, a day’s shorter illness is no small feat.  of course, this is just a single, sponsored trial, with all the advantages to the “home team”, as it were.  Whether treatment with baloxavir can be demonstrated to decrease clinically important deterioration remains to be seen – as has been a persistent struggle for other antivirals, given the low rate of complications, overall.  Then, even with rigorous screening, a third of those treated did not have influenza.  Real-world use would almost certainly include a greater proportion of patients without influenza.  Lastly, baloxavir-treated patients were observed to develop resistance mutations in substantial numbers, leading to questions whether this medication will provide durable efficacy in widespread use.

“Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716197

The Appendix Strikes Back

The classic, time-honored treatments for appendicitis are various forms of shamanism – swallowing lead balls, drinking pounds of quicksilver in hot water, or the application of slain young animals to the abdomen. The disease course of the classic patient, then, was obviously poor. In modern times, appendectomy. Ultra-modern, you might say, is antibiotics. Unfortunately, while the recurrence rate after appendectomy is quite low, short-term recurrence after antibiotics is disquietingly high – leading to additional questions regarding the durability of cure.

So, here are the 5-year outcomes of those patients initially entered into the APPAC randomized clinical trial. There were 530 patients randomized between 2009 and 2012 to either appendectomy or antibiotic therapy. Of the initial 257 randomized to antibiotics, 256 completed 1 year follow-up, 70 (27.3%) with recurrent appendicitis. Now, at 5 years, 246 were contacted for follow-up, with an additional 30 having undergone appendectomy. All told, this brings the total to a failure rate of 39.1% of antibiotic therapy in the original cohort. These authors also report quality-of-life and complication outcomes, but, as with the original trial, these are skewed because the initial cohort routinely underwent open appendectomy rather than laproscopic.

So, it seems as though the appendix, once identified as misbehaving, is prone to do it again. This does not disqualify antibiotics-first as a viable strategy for the treatment of uncomplicated acute appendicitis, but it would seem the long-term durability is more a coin flip rather than a roll of the dice.  That said, as long-term data grows more robust, it continues to push us in the direction of at least offering the option to our patients.

“Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2703354

Clearing the Cervical Spine with Distracting Injuries

Ah, the “distracting” injury. An utterly subjective and modifiable component of cervical spine clearance in the NEXUS criteria. Is it an isolated finger dislocation? Is it a femur fracture? We’ve all seen patients writhing or stoic in the face of either. And, then, factor in any prehospital analgesia ….

This is a prospective, observational study coming out of the American Association for the Surgery of Trauma evaluating the effects of distracting injury on cervical spine clearance. For their purposes, the following injuries were considered “distracting”:

Skull fracture, >2 facial bone fractures, mandible fracture, intracranial hemorrhage (including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, intraventricular hemorrhage, intraparenchymal hematoma), >2 rib fractures, clavicle fracture, sternal fracture, pelvic fracture, thoracolumbar spine fracture, intra-abdominal injury (including solid organ injury, hollow viscus injury, or diaphragmatic injury), femur fracture, tibia/fibula fracture, humerus fracture, radius/ulna fracture, and hip or shoulder dislocation.

The physical exam consisted of midline neck palpation and, absent any contraindication, active range of motion of the neck in flexion, extension and rotation. The cervical collar could be removed at the discretion of the treating team, but – in classic traumatology fashion – all patients underwent CT of the cervical spine, regardless of exam.

There were 2,929 blunt trauma patients with GCS ≥14, and 222 had cervical spine injuries identified on CT. Of these injuries, 25 were “missed” by the clinical exam. The “good news”: the rate of miss was “the same”, regardless of distracting injury – 0.7% vs. 1.3%. The bad news, of course, is that a normal physical examination missed 11% of cervical spine injuries. One patient whose injury would have otherwise been missed by a negative physical examination underwent operative intervention.

While there is some obvious spectrum bias associated with any observational cohort enrolled at trauma centers, it is still a reasonable estimate of the sensitivity and specificity of the physical examination. Clearly, it’s not bulletproof in the context of multi-system trauma – but, depending on the pretest likelihood of a cervical spine injury based on other presenting features, a distracting injury need not disqualify a patient from clinical clearance.

“Clearing the Cervical Spine in Patients with Distracting Injuries: An AAST Multi-Institutional Trial”

https://journals.lww.com/jtrauma/Abstract/publishahead/Clearing_the_Cervical_Spine_in_Patients_with.98558.aspx

Tenecteplase vs. Alteplase For … Stroke Mimics?

Bless their little hearts.

It’s almost as though this is a submission fo the IgNobel Prize, rather than a serious scientific manuscript. “How well does a medicine work when the patient doesn’t have the disease?” is basically a joke, right?

Not in the magical world of stroke neurology, replete with its array of meretricious interventions.

This is a secondary analysis of NOR-TEST, a phase III trial comparing alteplase with tenecteplase. A few folks believe tenecteplase has superior fibrinolysis to alteplase, and therefore ought to be potentially favored in acute ischemic stroke. NOR-TEST, for what it’s worth, could not detect any statistically significant difference between the two.

What is notable in this trial, of course, is the 17% rate of stroke mimics. And, this is a Very Important publication comparing the safety of these two medications when given to patients inappropriately. And, of course, there is no difference. There were three cases of intracerebral hemorrhage and three cases of extracranial bleeding, none of whom – you know – died, but were clearly all unnecessary iatrogenic injury.

Some more interesting notes, at least, from their analysis of stroke mimics. The average NIHSS in this entire study was 4, with the IQR for mimics 2-6 and for acute ischemia 2-8. There’s no useful evidence to suggest thrombolysis is superior to placebo in this sort of mild stroke cohort, but, here we are. Absent this evidence, some neurologists make an argument based on the Get With the Guidelines-Stroke registry, observing many patients with mild stroke are ultimately unable to be discharged to home due to persistent disability. In the NOR-TEST cohort of mimics, however, only 79% were assessed to have mRS 0-1 at 3 months, while their treated stroke cohort achieved mRS 0-1 only 60% of the time.  It would seem the base rate of mimic- or mild-stroke disability is effectively as observed in the GWTG-Stroke registry, regardless of treatment.

In sum, these authors have basically provided us with an unwitting glimpse into how acute stroke treatment has gone utterly off the rails in Norway.  Now, I wonder if they’re related to the group trying to push tPA in less than 20 minutes ….

“Safety and predictors of stroke mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST)”

https://www.ncbi.nlm.nih.gov/pubmed/30019629

The Fluoroquinolone/Aortic Dissection Association

We’ve been hearing about elevated incidence of connective-tissue disorders in patients having been prescribed fluoroquinolones for quite some time, primarily in the context of tendonopathies. Now, with aortic dissection.

The differences are quite small, but probably real. This retrospective case-crossover from Taiwan included 1,213 patients hospitalized with aortic pathology, and compared their fluoroquinolone exposure with those who did not experience aortic dissection despite similar disease risk scores from a national database. Using their time-period referent design, patients were about twice as likely to have been exposed to a fluoroquinolone in the aortic pathology group.

This isn’t the only recent look at the association between fluoroquinolone exposure and aortic pathology. Combine this with the profound impact on gastrointestinal flora these broad-spectrum antibiotics have, and the reasons are just piling up to avoid fluoroquinolones whenever clinically reasonable.

“Oral Fluoroquinolone and the Risk of Aortic Dissection”
https://www.ncbi.nlm.nih.gov/pubmed/30213330

Starting Treatment on First-Time Seizures

We see a fair bit of ostensibly “first-time” seizure in the Emergency Department. With some room for nuance and debate, general practice is typically still to defer initiation of anti-epileptic therapy.

This decision analysis in the neurology literature ultimately comes to the alternative conclusion – initiation of AEDs is reasonable even absent a clear or likely diagnosis of epilepsy. Based on their cases and parameters regarding seizure recurrence, the degradation of quality-of-life relating to seizure recurrence, and the features of modern AEDs, these authors find in favor of initiation of AEDs. Specifically, they find the previous threshold of ≥60% or greater chance of seizure recurrence after a first seizure is likely too high, and 30-40% may be more reasonable.

These conclusions are appropriate, considering the decision analysis model parameters – but, of course, by definition they also depend on the validity of these parameters. Then, whether this decision analysis can be applied clinically in the Emergency Department is another question, considering the challenges with regard to determine whether a seizure is truly unprovoked. Regardless, as AEDs evolve, have fewer adverse effects, and reach generic status, more liberal strategies of AED initiation in the Emergency Department may be in our future.

“Antiepileptic drug treatment after an unprovoked first seizure: A decision analysis”
http://n.neurology.org/content/early/2018/09/12/WNL.0000000000006319

Adult Head CT Decision Instrument Showdown

Every country seems to have their own pediatric imaging rule for minor head trauma, featuring PECARN, CHALICE, and CATCH. Recently, a head-to-head-to-head comparison (no pun intended) found the clear winner was: clinical judgement in Australia and New Zealand. Adoption of any of the rules would not have reliably increased sensitivity, but all would dramatically increase imaging.

Now, what about adult head trauma? The same story of every-country-has-a-flavor seems to be the case, with the CT in Head Injury Patients rule, the New Orleans criteria, the Canadian CT Head rule, and the National Institute for Health and Care Excellence guideline. This time, we have the Dutch performing the comparison.

In this multicenter, observational study conducted in 2015 and 2016, the authors enrolled neurologically-intact patients aged greater than 16 years and presenting with blunt head trauma within 24 hours of injury. Clinical data with the elements necessary for each decision instrument were completed by treating clinicians and collected by study staff. Decisions to perform imaging were based on individual clinician discretion, but primarily based on the CHIP rule. Outcomes were ascertained by electronic record review.

There were 5,839 patients entered in their study database, 5,517 meeting eligibility criteria. At three centers, only patients undergoing CT were entered in the database, while the remaining six centers included a handful of patients who did not undergo CT. Obviously, this grossly limits the descriptive capacity of the study, as clearly a massive number of patients with minor head injury who did not undergo CT were not followed for outcomes.

Overall, 384 of the 3,742 patients undergoing CT had positive traumatic findings. Most were small skull fractures, but about half had intracranial bleeding of some variety or another, with a further 74 being judged potential neurosurgical lesions. The most sensitive of the decision instruments in this study was the New Orleans criteria, while NICE guidelines were the least. Of course, the New Orleans criteria also would have recommended CT in all but 189 patients, for a specificity of 4.2%.

Ultimately, there’s no clear “winner” in this study, and, unfortunately, there’s also no obvious superior “clinician judgement” comparison lurking. The underlying rate of imaging was effectively the same as CHIP, as this was the national guideline in the Netherlands at the time of the study. Whether this is the “best” depends on tolerance for risk and the reliability of their estimate of “potential neurosurgical lesion”. Then, regardless of the decision instrument chosen, each still recommends imaging in thousands of patients in order to pick up the few with positive findings. Considering data from children, it seems we ought to be able to do much better – but current practice does not appear to be moving in that direction.

“External validation of computed tomography decision rules for minor head injury: prospective, multicentre cohort study in the Netherlands”
https://www.bmj.com/content/362/bmj.k3527

Homeopathy and Cardiac Arrest

Following up on the most recently published prehospital trials, we’re going back to an article published a few months ago. We’ve seen the data regarding epinephrine versus placebo – some does something, nothing does nothing, but the benefit of either strategy is debatable. Is there a better way?

This little retrospective report looks at the middle ground – a “well, let’s try and give a little less” protocol implemented in the King County prehospital system. Moving from their original protocol based on 1mg dosing with intervals indicated by rhythm, they halved it to 0.5mg. This resulted in patients generally getting a mean dose of epinephrine of about 2.5-3mg per arrest, rather than the 3.5-4mg total prior to implementation.

Did any outcome – survival, or, more importantly, neurologically-intact
survival – change? Not reliably, no.

These data provide only the lowest level of evidence as applied to determining the most advantageous use of epinephrine in the prehospital setting. This neither confirms nor refutes the premise of their practice change, and provides little specific insight into where the serial dilution of epinephrine loses its potency. There may yet be a sweet spot where return of spontaneous circulation occurs with minimal collateral damage, but we’ll need to wait for future research to provide additional data.

“Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes”
https://www.ncbi.nlm.nih.gov/pubmed/29305926

The Great Prehospital Airway Debate

… is over! With another 12,000 patients included in two prospective, randomized trials, we’ve finally arrived at unassailable conclusions regarding optimal airway management in the context of out-of-hospital cardiac arrest.

Or, as usual, not.

These two trials, AIRWAYS-2 from the United Kingdom and PART from the United States, randomized paramedics and emergency medical services agencies to routinely providing either endotracheal intubation or a supraglottic airway. The details of both trials are a little bit different, but they are both effectively pragmatic approaches directing the first attempt at airway management in patients deemed eligible in non-traumatic OHCA.

AIRWAYS-2 enrolled over 9,000 patients while PART enrolled over 3,000, and their results were similar, but not precisely the same. The primary outcome for AIRWAYS-2 was “good outcome” (0-3) on the modified Rankin Scale at 30 days, which was achieved by the ETI cohort in 6.8% versus 6.4% with SGA. The primary outcome for PART was 72-hour survival, which was 15.4% in their ETI cohort versus 18.3% with SGA. For rough comparison’s sake, PART also recorded mRS at hospital discharge, which was 5.0% with ETI and 7.1% with SGA.

These are both incredibly messy trials with regard to delivery of the intervention. Substantial fractions of both cohorts in the AIRWAYS-2 trial did not ultimately receive an attempt at an advanced airway, including over a quarter of those randomized to ETI. Then, the success rate for ETI in PART was only 51%, as compared with 90% with SGA. It is an imposing task to parse through their flow diagrams of randomization, patient interventions, and outcomes in both the main body of the articles and in the supplemental material.

Ultimately, while these can be argued back-and-forth due to substantial underlying uncertainty, there is little evidence to suggest ETI should be favored over SGA. This ought not be terribly surprising, as we’ve already seen a trial of ETI versus bag-valve mask ventilation which was unable to conclusively support one method over the other. While these findings probably could be used to substantially affect paramedic training and procedures with respect to ETI, the better, remaining question is whether any advanced airway should be routinely attempted at all.

“Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698493

“Effect of a Strategy of Initial Laryngeal Tube Insertion vs Endotracheal Intubation on 72-Hour Survival in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698491

“Autoimmune Encephalitis”? Eh?

Despite its rarity, this is an interesting topic to cover for a couple of reasons. First, in one of my health system administrative roles, I’ve noticed a large uptick in evaluation for this entity. And, then, second, it was picked up by the NEJM Emergency Medicine Journal Watch. So, paradoxically, the purpose here is both to heighten awareness of this disease process while at the same time throwing cold water on it.

The hullabaloo is all about autoimmune encephalitis – and the subset involved in this study concerns the typical onset after herpes simplex encephalitis. A non-trivial number of patients recover from an initial HSV encephalitis only to have recurrence of seizures and/or cognitive decline. Some of these cases can be attributed to reactivation of latent virus, while the others were of uncertain etiology. It now seems clear there is a significant autoimmune link, with increasing reports of antibodies against synaptic receptors detected in CSF.

In part of this very small, prospective study out of Spain, they identified 51 index cases of HSV encephalitis. None of these patients had neuronal antibiodies present at the index presentation.  However, within one year follow-up, a quarter developed new onset encephalitis with neuronal antibodies detectable in the CSF, primarily NMDA-receptor type. The typical presenting features of these patients differed between young children and adults, but most notably included seizures, behavior changes, and psychosis.

Recognition of this disorder is important because patients can have profound improvement with treatment and immunosuppression. That said, this is still an uncommon complication of a fairly rare disease – it took these authors 3 years to prospectively enroll their 51 patients, and even their retrospective case review across 6 years only managed to pick up 48 patients. These antibody responses are extremely rare, and recency bias should not dramatically change your practice. However, in the context of new-onset psychosis, an LP may be reasonable – and, if the remainder of the clinical evaluation supports it, antibody testing could dramatically alter treatment in a small cohort of patients.

“Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis”
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30244-8/fulltext