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”

Idarucizumab, the Sequel

There’s nothing hotter than idarucizumab, the reversal agent for dabigatran. It’s so hot, the New England Journal of Medicine once published a farcical 91 patient interim analysis of a planned 500 patient enrollment.  Now, two years later, we have the full cohort and it’s, well, more of the same, with all the flaws previewed in the previous iteration.

To recap, there are no viable reversal options for dabigatran besides this antibody fragment. And, in full sucker-born-every-minute fashion, Boehringer Ingelheim is both good cop and bad cop, selling us both the poison and the antidote.

There are 503 patients enrolled in this open-label study with two arms: Group A, with uncontrolled bleeding, or Group B, anticoagulated and requiring an urgent procedure. The primary outcome is, essentially, utterly unrelated to any of the context of enrollment – “maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab”, which is frankly already well-documented in the healthy-volunteer pharmacokinetic studies.

Theoretically, the interesting portion here is supposed to be the clinical relevance of the reversal effect – which is measured by secondary outcomes of subjective assessment of median time to cessation of bleeding in Group A or by periprocedural hemostasis in Group B. The most striking result in the interim result was a median time to cessation of bleeding of 11.4 hours – a concerningly high number calling into question the entire purpose of reversal. In this new publication, the median time to reversal is now reported as 2.5 hours. This also, oddly, differs from nearly identical cohort results presented to the American Heart Association – explicitly broken down as shown below:

Then, compare with this slide passed along by @bloodman from #ISTH2017 in Berlin:

Considering this was an easily critiqued result – and essentially the most clinically relevant – it’s not surprising the sponsor and their funded- and fee-supported collaborators solved the issue in the most expeditious fashion possible: exclude >55% of Group A from time-to-bleeding assessment.  Just toss out the patients who didn’t have cessation of bleeding within 24 hours, or – despite inclusion criteria of “signs and symptoms of (overt) uncontrolled bleeding” – the “bleeding location could not be identified”.

Most (93.4%) of patients in Group B were assessed as having normal hemostasis during their procedures, which occurred a median of 1.6 hours after completion of idarucizumab infusion. That said, many of the procedures were minimally invasive (catheter placement for dialysis, lumbar puncture, cutaneous abscess drainage) and likely favorably influenced both the fraction reported having normal hemostasis, as well as driving down the time to the intended procedure.

About 10% of the cohort had normal hemostasis at baseline as judged by the central laboratory, meaning they were likely not taking the dabigatran as reported or suspected – a smaller percentage than the interim analysis, where almost 25% were not. Whether this reflects better enrollment screening, or simply moving the goalposts again, cannot be reliably discerned from the results provided. Adverse events relating to the study drug, likewise, are difficult to parse without a true unexposed comparator.  Most of the cohort was elderly, with multiple comorbid conditions, in addition to their serious bleeding event or need for urgent procedural intervention. A handful of early thrombotic events and hypersensitivity-type reactions occurred, demonstrating there may yet be some consequential, but poorly quantified, risk to idarucizumab administration.

But, hand-wringing aside, we’re in the same place we were yesterday. Idarucizumab clearly and effectively removes dabigatran from circulation, unlike andexanet alfa and Factor-Xa inhibitors, and this ought to be occasionally clinically useful. I would certainly exhaust all potential supportive and expectant management options first, as well as try to definitively confirm dabigatran as the culprit for abnormal hemostasis. Ultimately, the best way to avoid idarucizumab? Don’t use dabigtran in the first place.

“Idarucizumab for Dabigatran Reversal — Full Cohort Analysis”

Nothing But Advantages to Treating Stroke Mimics!

What is the acceptable rate of treatment of stroke mimics with tPA? Zero? A few percent?  No limit?  It’s mostly harmless, after all – with only a ~1% rate of intracerebral hemorrhage. And, thanks to the free-market forces of comparison shopping and collective bargaining power of individual stroke patients, the cost of alteplase has increased >100% in the past decade to ~$6400 per dose. With all this going for it, it’s no wonder the American Heart Association gives a Class II recommendation for empirically treating, rather than pursuing additional diagnostic tests.

The added bonus – the more mimics you treat, the better your stroke outcomes appear!

This retrospective review of 725 tPA-treated patients at three hospitals evaluated the difference in rate of treatment of stroke mimics at an MRI-based “hub” hospital and CT-based “spokes”. Of 514 patients treated at the hub, only 3 (0.3%) were ultimately given a non-stroke diagnosis. Of 211 treated at the spokes, 33 (16%) were stroke mimics. The authors also noted, splitting their review period into 2005-09 and 2010-14, the rate of treatment of stroke mimics at spokes had increased from 9% to 20%.

To no great surprise, clinical outcomes – as measured both by mRS ≤1 five days after discharge and hemorrhagic transformation – significantly favored the spoke hospitals. Outcomes also improved between the time periods compared – hand-in-hand with the increase in treatment of stroke mimics.

These authors go on to mention treatment of stroke mimics has real financial cost to the health system and to individual patients, the misdiagnosis of stroke notwithstanding – growing ever more important as our health system lurches back towards penalties for pre-existing conditions. The authors acknowledge the luxury of having rapid MRI available for stroke, but go on to implicate aggressive efforts to improve door-to-needle times as contributing to misdiagnosis and harmful waste.

But, none of that matters when you can get a shiny promotional merit badge for your stroke center!

“Effects of increasing IV tPA-treated stroke mimic rates at CT-based centers on clinical outcomes”

I&D Alone or With Antibiotics for the Little Guys

Most physicians provide adjunctive antibiotic therapy for large abscesses following incision and drainage – the sorts where you need a bucket and a hose. Less clear has been the small abscess – but, in the age of MRSA, the fear factor has led many to cover these, regardless. Recent evidence suggests there is a small absolute benefit to antibiotic use and clinical cure, with an NNT around 14, along with other apparent benefits regarding re-infection and spread to household contacts. These trials, however, still enrolled patients with abscesses much larger than typically encountered in routine practice.

This trial is specifically designed to break the glass on “smaller skin abscesses” – just like in the title! What does small mean to these authors? It means a suppurative cavity of 5cm in diameter, or, up to the size of a cupcake:
abscess cakeSo, before we even start, we can see we may end up with issues regarding generalizability to many of the abscesses we encounter in the Emergency Department.

This trial is comprised of three arms – clindamycin, trimethoprim-sulfamethoxazole, and placebo – and enrolled 786 patients in an attempt to detect a 10% difference between arms while accounting for 20% attrition rate. The primary outcome was test of cure at 10 days after therapy, with a variety of secondary outcomes, including new infections at one month and treatment-related adverse events.

The winner, if one can be crowned, was not placebo. At the test of cure visit in the intention-to-treat population – and likewise, the population that could be evaluated – placebo lagged behind both clindamycin and TMP-SMX by approximately a 12% absolute magnitude of difference. Recurrent infections at the same site, or another site, were lowest in the clindamycin group at 6.8% – and similar between TMP-SMX and placebo, at 13.5% and 12.4%, respectively. However, clindamycin was implicated in the highest rate of adverse events, at 21.9%, compared with TMP-SMX and placebo, at 11.1% and 12.5%, respectively. Most of the difference in adverse events can be attributed to diarrhea illness, although clostridium difficile was not isolated in any cases. There was one case of systemic hypersensitivity reaction thought to be related to TMP-SMX.

There were two main drivers for the difference in test of cure between the placebo cohort and the two antibiotic cohorts, and these were use of rescue antibiotics during the follow-up period and new infections at another site. The use of rescue antibiotics is not necessarily a reliable measure of treatment failure, but it is still reasonable to suggest this difference would not arise by chance alone, despite the small sample. Regarding generalizability to practice, the minority of abscesses were cupcake-sized, but these were still fairly substantial infections. The median size of the abscess was about 2.2cm in diameter, with surrounding erythema of 5.9cm in greatest dimension.

The takeaway, then, hinges on the generalizability of their population to your individual patient. If these are “smaller” skin abscesses, then I wager the bulk of my abscess encounters are for “tinier” abscesses. I doubt this changes much current practice with regard to antibiotics, or antibiotic selection, for those treating abscesses in the 2+cm range, but I expect the differences in cure rates shrink for smaller lesions. It falls within the realm of acceptable practice variation to weigh the harms of antibiotic use with the chance of recurrence or new infection for those lesions.

“A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses”

Questioning the Benefit of Non-Invasive Testing for Chest Pain

Welcome to the fascinating world of instrumental variable analysis!

This is a retrospective cohort analysis of a large insurance claims database attempting to glean insight into the value of non-invasive testing for patients presenting to the Emergency Department with chest pain. Previous version of the American Heart Association guidelines for the evaluation of so-called “low risk” chest pain have encouraged patients to undergo some sort of objective testing with 72 hours of initial evaluation. These recommendations have waned in more recent iterations of the guideline, but many settings still routinely recommend admission and observation following an episode of chest pain.

These authors used a cohort of 926,633 unique admissions for chest pain and analyzed them to evaluate any downstream effects on subsequent morbidity and resource utilization.  As part of this analysis, they also split the cohort into two groups for comparison based on the day of the week of presentation – hence the “instrumental variable” for the instrumental variable analysis performed alongside their multivariate analysis. The authors made assumptions that individual patient characteristics would be unrelated to the day of presentation, but that downstream test frequency would. The authors then use this difference in test frequency to thread the eye of the needle as a pseudo-randomization component to aid in comparison.

There were 571,988 patients presenting on a weekday, 18.1% and 26.1% of which underwent some non-invasive testing within 2 and 30 days of an ED visit, respectively. Then, there were 354,645 patients presenting on a weekend, with rates of testing 12.3% and 21.3%. There were obvious baseline differences between those undergoing testing and those who did not, and those were controlled for using multivariate techniques as well as the aforementioned instrument variable analysis.

Looking at clinical outcomes – coronary revascularization and acute MI at one year – there were mixed results: definitely more revascularization procedures associated with exposure to non-invasive testing, no increase in downstream diagnosis of AMI. The trend, if any, is actually towards increased diagnoses of AMI. The absolute numbers are quite small, on the order of a handful of extra AMIs per 1,000 patients per year, and may reflect either the complications resulting from stenting or a propensity to receive different clinical diagnoses for similar presentations after receiving a coronary stent.  Or, owing to the nature of the analysis, the trend may simply be noise.

The level of evidence here is not high, considering its retrospective nature and dependence on statistical adjustments.  It also cannot determine whether there are longer-term consequences or benefits beyond its one-year follow-up time-frame. Its primary value is in the context of the larger body of evidence.  At the least, it suggests we have equipoise to examine which, if any, patients ought to be referred for routine follow-up – or whether the role of the ED should be limited to ruling out an acute coronary syndrome, and the downstream medical ecosystem is the most appropriate venue for determining further testing when indicated.

“Cardiovascular Testing and Clinical Outcomes in Emergency Department Patients With Chest Pain”

Diving to Save Lives

Hyperbaric oxygen therapy is easily as controversial a topic in Emergency Medicine as any. Many physicians and scientists believe HBOT is an essential treatment for carbon monoxide poisoning, with a goal toward restoring normal intracellular physiology as rapidly as possible. Other skeptics, however, point to the paucity of high-quality evidence in support of a logistically complex and expensive intervention.

This is a retrospective review from Taiwan evaluating outcomes of 25,737 patients recorded in their national health database as suffering from carbon monoxide poisoning. Of these, 7,278 patients received HBOT while the remaining 18,459. There were many significant and relevant differences between cohorts, with those not receiving HBOT tending to be older and have more medical comorbidities. On this substrate, unsurprisingly, the authors find a survival advantage – persisting through multivariate statistical adjustment – to receiving HBOT, with an adjusted hazard ratio of 0.74 (95% CI 0.67-0.81).

Despite the size of their sample, it is unlikely these data reflect a true treatment effect from HBOT. In a retrospective cohort such as this, the pervasive differences between groups almost certainly suggests confounding features influencing treatment decisions. Off the limited structured data recorded in this database, it is unlikely any statistical adjustment or matching technique will provide a better reliable estimate of any true mortality benefit – nor is a mortality benefit one of the expected outcomes of HBOT.

The authors also spend some time reporting the survival advantages associated with receiving HBOT more than once over the first month following the poisoning event. These positive findings are, effectively, the definition of survivorship bias – mortality directly affects the ability to receive multiple treatments. You can’t dive the dead, of course, so simply surviving to undergo additional treatments is erroneously associated with a benefit.

The authors eventually state “The results provide important references for decision making in the treatment of COP” – but, unfortunately, they tell us very little. The level of evidence supporting or refuting treatment with HBOT remains poor until an RCT of sufficient scale can be performed.

“Hyperbaric oxygen therapy is associated with lower short- and long-term mortality in patients with carbon monoxide poisoning”

The Door-to-Lasix Quality Measure

Will [door-to-furosemide] become the next quality measure in modern HF care? Though one could understand enthusiasm to do so ….


No one would understand such enthusiasm, despite the hopeful soaring rhetoric of the editorial accompanying this article. That enthusiasm will never materialize.

The thrills stacked to the ceiling here are based on the data in the REALITY-AHF registry, a multi-center, prospective, observational cohort designed to collect data on treatments administered in the acute phase of heart failure treatment in the Emergency Department.  Twenty hospitals, mixed between academic and community, in Japan participated.  Time-to-furosemide, based on the authors’ review of prior evidence, was prespecified as particular data point of interest.

They split their cohort of 1,291 analyzed patients between “early” and “non-early” furosemide administration, meaning within 60 minutes of ED arrival and greater than 60 minutes. Unadjusted mortality was 2.3% in the early treatment group and 6% in the non-early – and similar, but slightly smaller, differences persisted after multivariate adjustment and propensity matching. The authors conclude, based on these observations, the association between early furosemide treatment and mortality may be clinically important.

Of course, any observational cohort is not able to make the leap from association to causation.  It is, however, infeasible to randomize patients with acute heart failure to early vs. non-early furosemide – so this is likely close to the highest level of evidence we will receive.  As always, any attempt at adjustment and propensity matching will always be limited by unmeasured confounders, despite incorporating nearly 40 different variables. Finally, patients with pre-hospital diuretic administration were excluded, which is a bit odd, as it would make for an interesting comparison group on its own.

All that said, I do believe their results are objectively valid – if clinically uninterpretable. The non-early furosemide cohort includes both patients who received medication in the first couple hours of their ED stay, as well as those whose first furosemide dose was not given until up to 48 hours after arrival.  This probably turns the heart of the comparison into “appropriately recognized” and “possibly mismanaged”, rather than a narrow comparison of simply furosemide, early vs. not.  Time may indeed matter – but the heterogeneity of and clinical trajectory of patients treated between 60 minutes and 48 hours after ED arrival defies collapse into a dichotomous “early vs. non-early” comparison.

And this certainly ought not give rise to another nonsensical time-based quality metric imposed upon the Emergency Department.

“Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure”