Tylenol & Case of the Flawed Fetus

If you’re like most folks advising pregnant patients on pain and fever control, you’ve advised against ibuprofen and recommended acetaminophen. It is, after all, considered to be generally safe throughout pregnancy, in contrast to the alternatives.

I’m afraid I do not know precisely what to make of this study, but it is the latest in a context of several other studies linking maternal acetaminophen use during pregnancy with behavioral issues in young children. These authors link surveys of pregnant women performed over a decade ago with follow-up surveys of their children, with specific emphasis on identifying potential cofounders for their observed association.

The ultimate conclusion is fairly clear from just the title, with the subtitle of “Evidence Against Confounding”. An association is clearly observed between those they identify with likely or confirmed usage of acetaminophen and increased behavioral and attention difficulties in childhood. However, the evidence against confounding is rather incomplete. There are small differences in maternal psychiatric illness, maternal smoking, and maternal alcohol use favoring normally behaved children – and, while these authors attempt to control for these factors, this still introduces some element of statistical tomfoolery. There are also several non-genetic and non-prenatal risk factors for ADHD, and these authors are able only to collect a handful of these – absent completely any observations of the home environment of the children evaluated. Finally, no dose-response relationship is ultimately measured, as well.

I would, of course, ultimately advise minimal medication exposure in pregnancy, regardless. If pain control is necessary, it is not clear this risk – if true – is specifically of greater magnitude than those associated with alternative analgesia. For, this does not yet change practice.

“Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood”


The High-Sensitivity Troponin Ennui

They’re coming. It’s inevitable. They have yet to be approved in the the United States, but every year the news is the same: they’re coming.

High-sensitivity troponins have been both lauded and mocked from various perspectives. The literature is replete with examples of expedited rule-outs in the Emergency Department owing to their improved lower limit of detection for myocardial injury. However, every study touting the benefits of improved sensitivity has begrudgingly or worse acknowledged the correspondingly diminished specificity.

This, then, is a randomized trial of reporting either a conventional troponin assay result or a high-sensitivity troponin assay result, with a multitude of patient-oriented short- and long-term outcomes measured. The specific assays used here were either a c-TnT with a threshold of detection of 30 ng/L, or a hs-TnT with a threshold of detection of 3 ng/L. Clinicians caring for patients were randomized to making care decisions based on one, without knowledge of the other.

For all the various propaganda for and against high-sensitivity troponins, this trial is highly anticlimactic. There were, essentially, no changes in physician behavior resulting from the additional information provided by the more sensitive assay. No fewer patients were admitted, similar numbers of ultimate downstream tests occurred, and there were no reliable differences in long-term cardiac or combined endpoint outcomes.

The only outcome of note is probably consistent with what we already knew: any circulating troponin portends worse outcomes. This may be most helpful in directing the long-term medical management of those whose troponin levels were previously undetectable with a conventional assay; these patients clearly do not have the same virtually-zero risk as a patient with undetectable troponin levels. Indeed, troponin levels alone were a better predictor of long terms outcomes than the Heart Foundation Risk Stratification, as well.

I’ll let Judd Hollander sum it up in his most concise – with a link to much more verbose – terms:

“Randomized Comparison of High-Sensitivity Troponin Reporting in Undifferentiated Chest Pain Assessment”

Your New Career in “Waiting Room Medicine”

A few years back, a facetious advertisement in the Canadian Journal of Emergency Medicine promoted the availability of fellowship positions in “Waiting Room Medicine”, a comedic take on the struggles of the specialty to manage increasing patient volume with limited resources. While there are certainly Emergency Departments with ample space and “white glove”-type service – see the for-profit expansion of free-standing EDs in states like Texas – there are also publicly-funded and other EDs that struggle with physical bed space for patients for a variety of reasons.

This study attempts to quantify the effect of an intervention utilized by many overburdened or otherwise saturated EDs – starting the initial evaluation in triage with either provider-directed or protocolized orders. At UCLA/Olive-View, all patients presenting to an already-full ED received an initial rapid evaluation by an attending physician or nurse practitioner. During their 10-month study period, non-pregnant adults with abdominal pain were randomized to either receiving initial evaluation orders following this evaluation, or to be returned to the waiting room to await full evaluation at a later time pending bed availability.

There were 1,691 enrolled and randomized, with approximately 10% excluded from analysis mostly because they left the ED before their evaluation was complete. Overall, the initiation of the work-up in triage saved patients approximately a half-hour, on average, of bedded time in the ED. This was reflected by a similar absolute decrease in overall ED length-of-stay. There were a couple other interesting tidbits unique to their execution:

  • The most profound difference associated with WR medicine was simply blood and urine testing. While imaging could be ordered up front, it was rarely done.
  • Some of the advantages related to the WR blood testing were minimized by ~13% of patients receiving further testing after being bedded in the ED.
  • Patients randomized to WR medicine received, on average, a greater number of diagnostics per patient, probably representing resource waste.

So – yes, this probably accurately reflects the impact of orders placed in triage: some wasted resources based on the initial, incomplete evaluation, with a trade-off of potential time savings. The extent to which your system might benefit from a similar set-up is probably related to your level of chronic bed scarcity.

“Initiating Diagnostic Studies on Patients With Abdominal Pain in the Waiting Room Decreases Time Spent in an Emergency Department Bed: A Randomized Controlled Trial”

Shaking Out Stroke Mimics

In a world of continued aggressive guideline- and pharmaceutical-sponsored expansion of stroke treatment with thrombolytics, this article fills and important need – better codifying the predictors of stroke mimics. While other editorials espouse the need to be fast without being sure, this is frankly irresponsible medicine – and, in resource-constrained environments, unsustainable.

These authors at two academic centers performed a retrospective clinical and imaging review of 784 patients evaluated for potential acute cerebral ischemia. Patients were excluded if they had signs of acute stroke on initial non-contrast imaging, and if they did not subsequently undergo MRI. Based on review of the totality of clinical information for each patient, 41% of this cohort were deemed stroke mimics. The authors scoring system, then derived 6 variables – and 3 or more were present, the chance of stroke mimic being cause of the current presentation was 87.2%. Their criteria:

  • Absence of facial droop
  • Age <50 y/o
  • Absence of atrial fibrillation
  • SBP <150 mm Hg
  • Presence of isolated sensory deficit
  • History of seizure disorder

When the rate of tPA administration to stroke mimics is ~15%, and 30-40% of patients evaluated for stroke are stroke mimics – there is a lot of waste and potential harm occurring here. These authors suggest the use of this score could potentially halve these errant administrations for 94% sensitivity, or cut errant administrations down to 2% with 90% sensitivity. Considering the patients for which stroke/stroke mimic is an ambiguous diagnosis, it is reasonably likely the symptoms are of lesser severity – and in the range for which tPA is of most tenuously “proven” value. While their rule has not been prospectively validated, some of these elements certainly have face validity, and can be incorporated into current practice at least as a reminder.

“FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department”


Save the FFP, Save the World

This is a trial that does a couple things I really love: it nails inappropriate usage of the International Normalized Ratio to the wall, while simultaneously offering a viable alternative.

The INR is intended for one thing and one thing only: monitoring anticoagulation with warfarin. The INR, as a proxy for the PT, has instead been utilized as a pointless and misleading instrument for screening adults for previously undiagnosed coagulopathy. The PT, in the correct, narrow clinical context, has value – the INR does not.

This trial beautifully illustrates this point. These are patients with severe cirrhosis and end-stage liver disease undergoing invasive procedures. With thirty patients in each group, they were randomized to either standard pre-procedure prophylactic transfusion per-protocol based on INR guidelines, or the necessity of blood product was determined via thromboelastography. In the standard care group, the mean INR was 2.01, and, thus, per protocol, the typical patient received an appropriate dose of 4 units of FFP for “correction”. In the TEG group, only a handful of patients were deemed to actually have a coagulopathy for which FFP was indicated. No patients in the TEG-guided cohort had procedure-related bleeding and identical numbers of patients needed red cell transfusions.

Transfusions are expensive and dangerous: transfusion-related circulatory overload, transfusion-related lung injury, various incompatabilities and allergic reactions are not terribly infrequent. They should be avoided whenever possible, and this study beautifully illustrates the disutility of the INR for screening for bleeding risk. ESLD patients have elevated INRs from their inability to synthesize Vitamin K-dependent clotting factors, but they also do not synthesize Protein C and S, and there are a variety of other compensatory mechanisms. These patients do not routinely need transfusions of FFP prior to procedures, despite most centers being replete with similar protocols.

“Thrombelastography-Guided Blood Product Use Before Invasive Procedures in Cirrhosis With Severe Coagulopathy: A Randomized, Controlled Trial”

Don’t Stop at the Headline

The verdict is in: “Aspiration Thrombectomy No Help for Large-Clot Strokes”, reports MedPage Today.

Except, they’re not precisely correct – in a way, you could even say they’re wrong.

This is THERAPY, an endovascular trial in acute stroke featuring the Penumbra aspiration device.  This is somewhat unique, as the technology differs from the otherwise popularized Solitaire retrieval system. This trial is also different from the most contemporary comparators, as its imaging criteria did not rely on perfusion imaging, but, rather, simply large-vessel occlusion with a clot length of 8mm or greater.

The results of the trial, as you might have picked up from the lay press headline, were negative – that is to say, they did not reach statistical significance. Their primary endpoint for modified Rankin Scale of 0-2 was achieved in 38% receiving endovascular treatment and 30% receiving intravenous thrombolysis alone, and this 8% absolute difference produced a p-value of only 0.52. However, the trial was initially scheduled to enroll 692 patients to be powered to detect a 10.6% difference, but stopped enrollment after 108 based on the publication of other positive endovascular trials.

So, simply put, this trial tells us hardly anything. Is the Penumbra system just as good as Solitare? Probably, but perhaps we’ll never know for certain. Does the 8% difference seen in this trial reflect the lower magnitude of effect of treatment relating to lack of perfusion imaging? Probably, as well, based on the the larger evidentiary context.

But, at the minimum, the medical reporting has simply gone off course with their headline.

“Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone”

Dawn of the Stat Acupuncture Consult

For thousands of years, a smattering of herbology, naturopathy, and non-pharmacologic treatment formed the mainstay of medical practice. With recent seismic shifts away from vaccines and other pillars of medical therapy – will we remember the 20th century as the apex of the pharmacologic era of medicine?

This is a randomized, unblinded trial comparing morphine against acupuncture for acute pain syndromes in the Emergency Department. Patients were recruited with, essentially, severe pain without serious underlying illness – sprains, low back pain, headaches, renal colic and dysmenorrhea. Patients were treated with either 0.1mg/kg morphine with additional 0.05mg/kg doses every 5 minutes or protocolized acupuncture performed by an experienced practioner (who also happened to be an Emergency Medicine physician).

There were three hundred patients included in this trial, and there were a few differences between groups – the morphine group tended to have more abdominal pain, while the acupuncture group skewed towards low back pain. Regardless, the acupuncture group achieved similar – or better – pain relief than the morphine treatment arm. There were no major adverse events in either arm, although a little more than half of the morphine cohort experienced the typical minor effects of drowsiness or nausea.

Could it be prime-time for acupuncture? Probably not – one, small, single-center trial does not generalized across all practice settings. Additional validation should be performed – and, most importantly, a placebo effect needs to be excluded. However, this is quite the powerful placebo effect – and, at a minimum, should inspire further research on methods for triggering these same perceptual effects within the context of our current treatment modalities.

“Acupuncture vs intravenous morphine in the management of acute pain in the ED”

The Extra Head CTs in Trauma, Estimated

In the world of academia and residency training, the spirited debate in trauma is usually regarding the merits of the “pan-scan” – and whether we can all agree it is probably safe to reduce costs and resource utilization by selective scanning. In community practice, it’s about picking up the needle in a haystack – and, hence, preventing the innumerable unnecessary CTs.

This is a retrospective review using electronic health record data to estimate the number of potentially unnecessary head CTs in the setting of trauma. These authors pulled records for all patients for whom a head CT was obtained, and for whom recorded EHR values suggested an encounter for trauma. This cohort was then evaluated for appropriateness of a CT by retrospectively determining the presence of high-risk or exclusion criteria for the Canadian CT Head Rule.

Among 27,240 patients extracted, 11,432 (42.0%) were “discordant” with the CCHR by structured EHR content. However, upon manual review of the chart narrative, the structured EHR content misclassified the CCHR recommendation 12.2% (95% CI 5.6-18.8%) of the time. Thus, the authors then estimate approximately 36.8% (95% CI 34.1-39.6%) of CT head for trauma in a community setting is inappropriate.

This is probably a reasonable research strategy, warts and all. Due to EHR limitations, they actually only filtered for 3 of the 5 high-risk criteria – basilar skull fracture and open skull fracture are such rare findings in their cohort the impact on overall results would be negligible. Then, Kaiser is probably more aggressive at minimizing CT use than the general community ED population, as routine quality improvement monitors individual and group rates of CT usage.

Bottom line: at least a third of head CTs for trauma in the community can probably be obviated by use of validated criteria.

“Computed Tomography Use for Adults with Head Injury: Describing Likely Avoidable ED Imaging based on the Canadian CT Head Rule”


The Downside of Antibiotic Stewardship

There are many advantages to curtailing antibiotic prescribing. Costs are reduced, fewer antibiotic-resistant bacteria are induced, and treatment-associated adverse events are eliminated.

This retrospective, population-based study, however, illuminates the potential drawbacks. Using electronic record review spanning 10 years of general practice encounters, these authors compared infectious complication rates between practices with low and high antibiotic prescribing rates. Spanning 45.5 million person-years of follow-up after office visits for respiratory tract infections, there is both reason for reassurance and reason for further concern.

On the “pro” side, cases of mastoiditis, empyema, bacterial meningitis, intracranial abscess and Lemierre’s syndrome were no different between those who prescribed high rates (>58%) and those with low rates (<44%). However, there is a reasonably clear linear relationship with excess follow-up encounters for both pneumonia and peritonsilar abscess. Incidence rate ratios were 0.70 compared with reference for pneumonia and 0.78 compared with reference for peritonsillar abscess. However, the absolute differences can best be described as “large handful” and “small handful” of extra cases per 100,000 encounters

There are many rough edges and flaws relating to these data, some of which are probably adequately defeated by the massive cohort size. I think it is reasonable to interpret this article as accurately reflecting true harms from antibiotic stewardship. More work should absolutely be pursued in terms of strategies to mitigate these potential downstream complications, but I believe the balance of benefits and harms still falls on the side of continued efforts in stewardship.

“Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records”


The Febrile Infant Step-by-Step

You’ve heard of the Philadelphia Criteria. You’ve heard of the Rochester Criteria. But – Step-by-Step?

This is an algorithm developed by European emergency physicians to identify low-risk infants who could be safely managed without lumbar puncture nor empiric antibiotic treatment. After retrospectively validating their algorithm on 1,123 patients, this is their prospective validation in 2,185 – looking for IBI or “Invasive Bacterial Infection” as their primary outcome.

The easiest way to summarize their algorithm and results is by this figure:

Step by Step

Sensitivity and specificity, respectively, were as follows:

  • Rochester – 81.6% and 44.5%
  • Lab-score – 59.8% and 84.0%
  • Step-by-Step – 92.0% and 46.9%

The authors attribute 6 of the 7 missed by Step-by-Step to evaluation early in the disease process – presentation within 2 hours of onset of fever.

Their algorithm is reasonable at face validity, and could be incorporated into a protocol with close follow-up to re-evaluate those early in their disease process. We still have, however, a long way to go regarding specificity.

“Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants”