More Futility: Apneic Oxygenation?

Here’s another pendulum swing to throw into the gears of medicine – an apparent failure of apneic oxygenation to prevent hypoxemia during intubation in the Emergency Department. Apneic oxygenation – passive oxygenation during periods of periprocedural apnea – seems reasonable in theory, and several observational studies support its use. However, in a randomized, controlled ICU setting – the FELLOW trial – no difference in hypoxemia was detected.

This is the ENDAO trial, in which patients were randomized during ED intubation, with a primary outcome of mean lowest oxygen saturation during or immediately following. These authors prospectively enrolled 206 patients of 262 possible candidates, with 100 in each group ultimately qualifying for their analysis. The two groups were similar with regard to initial oxygen levels, pre-oxygenation levels, and apnea time. Then, regardless of their statistical power calculations and methods, it is fairly clear at basic inspection their outcomes are virtually identical – in mean hypoxemia, SpO2 below 90%, SpO2 below 80%, or with regard to short-term or in-hospital mortality. In the setting in which this trial was performed, there is no evidence to suggest a benefit to apneic oxygenation.

It is reasonable to note all patients included in this study required a pre-oxygenation period of 3 minutes by 100% FiO2 – and that oxygen could be delivered by bag-vale mask, BIPAP, or non-rebreather with flush rate oxygen. These are not necessarily equivalent methods of pre-oxygenation, but, at the least, the techniques were not different between groups (>80% NRB). It is reasonable to suggest passive oxygenation may be more beneficial in those without an adequate pre-oxygenation period, but it would certain be difficult to prospectively test and difficult to anticipate a clinically important effect size.

Adding complexity to any procedure – whether with additional monitoring and alarms or interventions of limited efficacy – adds to the cognitive burden of the healthcare team, and probably has deleterious effects on the most critical aspects of the procedure. It is not clear that apneic oxygenation reliably improves patient-oriented outcomes, and does not represent a mandatory element of rapid-sequence intubation.

“EmergeNcy Department use of Apneic Oxygenation versus usual care during rapid sequence intubation: A randomized controlled trial”

The Futility of NSAIDs for Back Pain?

This article filled with reproach for non-steroidal anti-inflammatories was highlighted in a New England Journal of Medicine Journal Watch and on Twitter – a wistful treatise remarking on the general ineffectiveness of pharmacologic analgesics. “Nothing works!” accompanied by a general gnashing of teeth and writhing on invisible flames.

But – does this meta-analysis actually reach such a conclusion? Examine the first few words in their conclusion:

NSAIDs are effective for spinal pain …

Off to a good start! But, the catch:

… but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important.

These authors pool the results of 35 randomized, placebo-controlled trials for “spinal pain”, which is to say undifferentiated pain relating anatomically to any part of the spine. These trials comprised 6,065 participants – or, if you do the math, an average of 173 patients per trial, nearly all of them performed over a decade ago. The pooled effects of these trials all favored NSAIDs – but, as the authors mention, the absolute magnitude of effect on pain scales was a the edge of their threshold for clinical significance. The authors defined a difference of 10 points on a 100-point scale as clinically important, but most of their pooled results landed between -7 and -16, favoring NSAIDs over placebo. With these small samples, generally moderate GRADE quality, and moderate to high heterogeneity between the pooled results, there is a lot of fuzziness around their ultimate conclusion.

These authors do many, other, exploratory analyses, and it is reasonable to suggest the limitations inherent to each render any conclusions unreliable. Adverse events, as reported, were similar between groups – excepting for increased gastrointestinal adverse events, most of which were non-serious. The authors report this difference as a relative risk of 2.5 for GI side effects in their comparison, but the absolute differences are on the order of an excess of 1 in 100.

This is probably much ado about nothing. Their perspective is not inaccurate, per se, but these trials do find a consistent benefit to NSAIDs. The value judgment here on clinical effectiveness probably misses the mark, particularly considering these are inexpensive, readily available, with few adverse effects in short-term use. I would probably argue it is easier to defend a position they still have utility in multi-modal pain control regimens, rather than to conclude they be consigned to the rubbish bin.

“Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis”


Predicting Treatment Failure in AOM

Like most infectious diseases, acute otitis media generally breaks down into three cohorts. There are viral infections, for which early antimicrobial therapy is virtually, by definition, unhelpful. Then, there are true bacterial infections – many of which resolve without substantial morbidity regardless of antimicrobial treatment, and those which require antimicrobial therapy to prevent such. The trick, and where modern medicine typically fails miserably, is rapidly predicting into which of these cohorts a patient may fall – a conundrum leading to the epidemic of antibiotic overuse.

This is a secondary analysis of a pediatric AOM trial, first published in the New England Journal of Medicine, looking at which patients were more likely to potentially fail conservative treatment. The intervention arm received amoxicillin/clavulanate, and treatment failure occured in 31.7% of children – vastly favoring the antibiotic arm – 44.9% vs. 18.6%. In theory, this exaggerated treatment effect might help better illuminate any small predictors – but, unfortunately, with only 319 patients, meaningful statistical significance on this data dredge is hard to come by. Worse still, the best predictor of treatment failure (or, really, lack thereof)? A peaked tympanogram (A and C curves) – you know, because we’re all routinely measuring tympanometry. Grossly bulging tympanic membranes were predictive of treatment failure, which has some face validity, at least – but, again, this is as compared between severe, moderate, and mild, which requires pneumatic otoscopy to differentiate.

The question here primarily concerns: can you take away good conclusions from bad data? The magnitude of the treatment effect seen in this trial far exceeded the treatment effect expected from antibiotics in other trials. And, consistent with that questionable generalizability, their findings reflect the stringent criteria determining their diagnosis of AOM. Then, they are relying upon their misguided definition for treatment failure, which relies on otoscopic signs, the same ones that will be colinear with worsened disease on initial examination. Unfortunately, the net result of all of this meandering is essentially no clinically useful insight. Considering the limitations the examination of the screaming ill toddler, more pragmatic approaches are necessary.

“Prognostic Factors for Treatment Failure in Acute Otitis Media”

Let’s Get Together and Ignore PERC

The “Pulmonary Embolism Rule-Out Criteria” does not, as it implies, “rule out” PE.  It does, however, generally carve out a cohort for whom objective testing may be obviated, with the implication the costs and harms from false-positives and from anticoagulation outweigh the morbidity from missed PE. It is fairly well popularized and incorporated into guidelines for PE – and, well, at the least, physicians in an academic center, on the cutting edge of medical knowledge and education, should be applying appropriately.

Or not.

This is a prospective study enrolling undifferentiated Emergency Department patients with chest pain and shortness of breath. Research staff approached patients with these general chief complaints and collected the baseline variables needed for PERC, Wells, and other baseline clinical and historical data.  They collected data on 3,204 patients, 17.5% of whom were PERC-negative. Of these, 25.5% underwent some testing for pulmonary embolism – inclusive of D-dimer, CTPA, or V/Q scanning. Then, two – 0.4% – PERC-negative patients were ultimately diagnosed with a PE. The authors also present comparative data for the PERC-positive population, with the expected higher-frequency of testing and diagnosis associated with the absence of low-risk features.

PERC is, of course, an imperfect tool, an unavoidable consequence of any decision instrument narrowing a complex clinical decision down to a handful of variables. But, at the least, patients meeting PERC ought nearly all fall into the bucket of “why were you really considering PE in the first place?”, with few exceptions. For nearly a quarter of these to start down the rabbit hole of testing for PE is low-value and harmful medical practice at a population level, regardless of the potential magnitude of individual benefit for those true positives ultimately identified.

AOr, more concisely, this is nuts.

“Pulmonary Embolism Testing among Emergency Department Patients who are Pulmonary Embolism Rule-out Criteria Negative”

When Can You Clear the Intoxicated Cervical Spine?

The answer is: it depends – are we talking about the “real world”, or the world of evidence-based medicine?

This is a qualitative survey and prospective, multi-center observational study of the cervical spine clearance practices following major trauma. Performed at 17 centers, these authors collected data on definitions of evaluability, length of time in cervical-spine immobilization, and the diagnostic characteristics of CT in the context of the intoxicated trauma patient.

These authors analyzed 10,191 patients, approximately 3,000 of whom were intoxicated with alcohol, drugs, or both. The median injury severity score was ~10, with about a quarter of the cohort having “severe injury” or ISS >15. Incidence of any identified cervical spine injury was 7.6%, or overall 1.4% clinically significant CSI. In this intoxicated cohort, the sensitivity and specificity of the CT was 98% and 93%, respectively. A long questionnaire regarding real-world practice is presented, and the responses are very interesting – most surveyed indicated they would not clear the patient until they were clinically sober for a reliable examination, and patients stayed in their cervical collars for up to 8 hours as a result. On the other hand, despite their practice to the contrary, a small majority of respondents indicated they believed it was safe and reasonable to clear the cervical spine following a CT.

The takeaway for us in the Emergency Department, however, is that it is definitely safe to do so. Absent the multi-system trauma and mechanisms involved in this study, our typical otherwise-uninjured intoxicated patient has a vanishingly small chance of significant injury missed on CT. The risks and costs of staying in the collar – including those of follow-up MRI – exceed the potential harms of a missed injury. If these authors, in the Journal of Trauma – despite their spectrum bias – ultimately conclude it is safe to remove the c-collar based on the NPV in their sample, it is even moreso for our less severely-injured general ED population.

“Cervical spine evaluation and clearance in the intoxicated patient: a prospective western trauma association multi-institutional trial and survey”

Even the Best EHR Still Causes Pain

Paper is gone; there’s no going back. We’re all on electronic health record systems (cough, Epic) now, with all the corresponding frustrations and inefficiencies. Some have said, however, the blame lay not with the computer – but with the corporate giant whose leviathan was not designed to meet the needs of physicians in the Emergency Department, but rather support the larger hospital and primary-care enterprise. Unfortunately, as we see here, even a “custom” design doesn’t solve all the issues.

These authors report on their experience with their own homegrown system, eDoc, designed to replace their paper system, and built using feedback from health technology experts and their own emergency medicine clinicians. Their hypothesis, in this case, was that throughput would be maintained – ED length-of-stay as a proxy for operational efficiency. The interrupted time series analyses performed before-and-after the transition are rather messy, with various approaches and adjustments, including “coarsened exact matching”, but the outcome is consistent across all their models: the computer made things worse. The estimated difference per patient is small: about 6 additional minutes, but, as the authors note, in a mid-size ED handling about 165 patients a day, this adds 16 hours of additional boarding time – or the effect of shrinking your ED in size by up to 2/3rds of a room.

It is probably erroneous to simply blame “computers” as the culprit for our woes. Rather, it is the computer-as-vehicle for other onerous documentation requirements and regulatory flaming hoops. If the core function of the EHR were solely to meet the information and workflow needs of physicians, rather than the entire Christmas buffet of modern administrative and billing workflow, it is reasonable to expect a moderation in the level of suffering.

But, I think that ship has sailed.

“A Custom-Developed Emergency Department Provider Electronic Documentation System Reduces Operational Efficiency”

Does Length of TTM Matter after Cardiac Arrest?

Targeted temperature management, sometimes conflated with therapeutic hypothermia, is part of modern resuscitation guidelines in post-arrest care. There are, however, many aspects of this therapy for which the details remain hazy, including: how long? 24 hours? 48 hours? Or, as in neonates, 72 hours?

This is the “Time-Differentiated Therapeutic Hypothermia” trial, a randomized, single-blind comparison between TTM – in this case, TH at 33°C – treatment for 24 hours versus 48 hours following resuscitation from cardiac arrest. These authors randomized 355 eligible survivors to ICU admission into two generally similar arms, most of whom received their assigned treatment without protocol violations. A great deal of data on survival, adverse events, and other secondary features are presented, and the short of it is: probably no difference. Similar proportions of patients in each arm had cerebral performance scores of 1 or 2 at six months, which was the primary outcome. Mortality at six months was also similar, as was, generally speaking, adverse events. Confidence intervals, however, were quite wide – for example, the relative risk for CPC 1 or 2 was 1.08 with 95% CI of 0.93 to 1.25, the top end of which represents a fairly meaningful difference. However, given the Bayesian pre-test likelihood of such an advantage, the null hypothesis is the clear winner. One clear loser: ICU length-of-stay, and by association, healthcare costs, which will obviously favor the group with a shorter period of TTM.

Some comments on Twitter were overjoyed at six-month survival figures approaching 70% as indicative of advances in post-arrest care. Unfortunately, these are more reflective of their exclusion criteria – which entailed non-cardiac causes of arrest, asystole rhythms, vasopressor-resistant shock, extended pre-ROSC resuscitation times, and a host of other items representing dire prognoses. These are the “best of the best”, which is reasonable to try and reduce heterogeneity and other random effects on outcome measures.

Lastly, it is reasonable to note one of the elements of causality generally entails a dose-response relationship, in which the magnitude of exposure to a beneficial therapy relates in some fashion a continuum of outcomes. Lacking such an apparent relationship, as in this trial, does not refute an association between TTM/TH and improved outcomes, but certainly continues to raise points regarding the precise elements of post-arrest care resulting in improved outcomes. Cooling to 33°C does not appear to confer an advantage to 36°C, nor does an extended exposure to the treatment. What is it really, then, that helps achieve the greater proportion of CPC 1 and 2 survivors?

“Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest”

Now It’s Fluids that Matter in Sepsis?

A few weeks ago, there was an article in the New England Journal of Medicine that dredged a retrospective data set to generate an association between timeliness different elements of a sepsis bundle and outcomes. In their analysis, antibiotics, but not fluid administration, was associated with a mortality increase. This has, at least, face validity – although, the association between timely blood cultures and serum lactate a little less so.

Now, conversely, we have another sepsis registry review attempting to tie time to fluid administration to mortality. This quality improvement registry prospectively identified patients with sepsis – and retrospectively abstracted their clinical data – between 2014 and 2016, resulting in a database of 11,182. In their analysis, mortality for patients receiving their first crystalloid within 30 minutes or within 30-120 minutes was ~18%, while mortality for patients whose fluids were initiated beyond the 120 minute limit was 24.5%.

Again, however, because these are comparisons performed on observational data, it is still subject to the slings and arrows of unmeasured confounders. Most patients whose fluid administration was started early had their care initiated in the Emergency Department – and, in clearly co-linear processes, had major elements of their care completed appropriately. This included repeat lactate measurements, antibiotics within 180 minutes of time zero, and, not only IVF within 120 minutes, but frankly, any IVF at at all. Nearly 60% of patients analyzed for their >120 minute cohort received <5 mL/kg or zero IVF in their first six hours from measurement time zero.

This is, probably, another study just cherry picking out one single feature of an entire process predicated on timely identification and treatment of sepsis. These patients did not simply have a mortality advantage because of the timeliness of IVF – it ties in to all aspects of care and attention given sepsis patients properly identified. The effect size here is probably less associated with delays just in IVF, but a comprehensive delay in diagnosis – and all its associated therapeutic misadventures.

“Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort”

Conjunctivitis: No Antibiotics, Please!

It’s the sad state of modern medicine – choose a common ambulatory condition, and you can find widespread avoidable overuse and waste. There is a spectrum of acceptability to this practice variation, of course, depending on the severity of consequences for missed or delayed diagnoses – but, for the most part, we’re just setting our professional respectability aflame.

This is a simple retrospective review of prescriptions associated with diagnoses of acute conjunctivitis. These authors reviewed records from a large managed care network and identified 340,372 patients with a clinical visit coded for acute conjunctivitis. Within 14 days of this visit, 58% of patients filled prescriptions for topical ophthalmologic medications. Considering most conjunctivitis encountered in the clinical setting is viral or allergic, obviously, the vast majority of these are wholly unnecessary. Then, frankly, while topical antibiotics mildly hasten the improvement of bacterial conjunctivitis, it is still a generally self-limited condition.

Ophthalmologists and optometrist visits were the least likely to have an antibiotic prescription associated with a visit for acute conjunctivitis, but 36% and 44%, respectively. Urgent Care Physicians and “Other Provider” – probably inclusive of Emergency Medicine – were at 68% and 64%, respectively. Fluoroquinolones accounted for 33% of antibiotic prescriptions – which is fabulous, because they are typically the most costly, and result in both increased risk for antimicrobial resistance and S. aureus endophthalmitis. Then, one in five prescriptions were for combination corticosteroid-antibiotic combination products – which are contraindicated, as they can prolong viral infections or worsen an underlying herpes simplex infection.

The American Academy of Ophthalmology contribution to Choosing Wisely recommends avoiding antibiotic prescriptions for viral conjunctivitis, and deferring immediate antibiotic therapy when the cause of conjunctivitis is unknown. Stop the madness! Everyone!

“Antibiotic Prescription Fills for Acute Conjunctivitis among Enrollees in a Large United States Managed Care Network”

The Shenfu Wave Continues

It was just a few months ago where I featured a brief review of Shenfu injection for the treatment of patients with septic shock. The conclusion: promising, yet – possibly because I’m simply culturally obtuse – a healthy dose of skepticism seems warranted.

This is another example of Shenfu injection in a randomized, controlled trial – this time for in-hospital cardiac arrest. Shenfu, just to recap:

Shenfu injection (SFI), produced by using multistage counter current extraction and macroporous resin adsorption technology, is a well-known TCM formulation containing ginseng (Panax; family: Araliaceae) and aconite (Radix aconiti lateralis preparata, Aconitum carmichaeli Debx; family: Ranunculaceae). Ginsenosides and aconite alkaloids are the main active ingredients in Shenfu.

In this trial, patients were randomized – in open-label fashion – to either a post-resuscitation bundle, or the same bundle plus twice-daily 100mg Shenfu infusions. Treatment was continued for 14 days or transfer out of the ICU, whichever came first.

These authors assessed 1,022 patients, 44 of whom were not randomized because consent could not be obtained. The remaining 978 were allocated to the two arms, approximately 35 of whom in each group died before receiving the study intervention. Baseline characteristics, adjudicated cause of arrest, presenting rhythm, and follow-up care were similar between the two groups. The most common rhythm, by far, was asystole, at ~82% of each group.

The winner, again, is the Shenfu injection cohort, by far. 28-day survival was 42.7% versus 30.1%, 90-day survival was 39.6% vs. 25.9%, median ventilation and hospital length of stay were ~4 days shorter, and hospital costs reflected these shorter time periods. Not only was survival improved, but a greater proportion of survivors were discharged with cerebral performance scores of 1 or 2, rather than with severe disability or coma.

There are obvious limitations, the lack of blinding for the treating physicians most potentially biasing. However, this is, again, a large effect size for a very meaningful outcome. Considering the other utter rubbish otherwise approved and marketed in modern medicine, it should be prioritized, to say the least, to further evaluate in a prospective fashion – particularly outside of China.

Now, if we wanted to get television-miracle levels of survival, we should just combine this with high-dose Vitamin C therapy!

“Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial”