Hypertonic Saline No Help for Bronchiolitis

There’s probably no common illness with quite so much flailing about in the evidence base than bronchiolitis.  Between bronchodilators, steroids, saline, and epinephrine, they’ve thrown the kitchen sink at it.  Some show potential benefit, while others do not.

This is another study following up the suspected benefit of nebulized hypertonic (3%) saline in reducing length of stay in hospitalized patients.  In a randomized trial, these authors enrolled 227 patients to receive either nebulized 3% saline or 0.9% saline placebo.  There were no important differences between patients randomized to each arm.  By all outcome measures – intensive care unit admission, objective deterioration of respiratory status, inpatient length-of-stay, or readmission – there was no difference between therapies.

The effect seen here – with seemingly contradictory results – is probably precisely as predicted by Ioannidis’ statistical theory regarding “Why Most Published Research Findings are False”.  Simply put, the prior probability of any of these treatments being helpful is quite low – and the extent of random bias associated most of these studies high.  The net effect, then, is the posterior probability associated with any significant finding is barely changed.

Nebulized hypertonic saline is probably harmless, but if it’s not helpful, it still doesn’t have a role.

“3% Hypertonic Saline Versus Normal Saline in Inpatient Bronchiolitis: A Randomized Controlled Trial”

The Unintended Harms of “Quality”

Harder!  Better!  Faster!  Stronger!  There is a proliferation of time-based measures in the Emergency Department – the glut of which funds a horde of administrative overhead, and for which the Center for Medicare and Medicaid Services will audit.  These measures must frequently seem relatively benign and commonsense when conceived – but their implementation is anything but.

This is a retrospective quality evaluation from the Christiana Health System, looking at their door-to-balloon time metric for STEMI.  Faster is better – of course – so, in 2009, an aggressive quality improvement intervention was performed to decrease delays and obstacles to cardiac catheterization.  As described in the article, this mostly seemed to consist of exhorting each step the process to be performed more rapidly, and providing additional feedback during the QI initiative.

And, it worked!  Median door-to-ballon time sank from 76 minutes to 61 minutes by 2010.

Unfortunately, this came at a cost: false-positive activations more than doubled.  Furthermore, the mortality rate of false-positive activations jumped from 5.6% to 21.6%.  The fatal alternative diagnoses included massive PE, intracranial hemorrhage, severe sepsis, and aortic dissection.

The authors go on further to describe a follow-up QI intervention of education and feedback regarding the missed diagnoses, and, over time, the mortality rate has improved.  However, false positives persist around 20% of activations – triple the original rate.

So, they’ve saved 15 minutes of door-to-balloon time – a probably clinically insignificant amount – at the cost of scads new false-positives and at least one substantial bump in mortality.  And, you know this is but _one_ of many time-based metrics invading – and harming patients in – the Emergency Department.

Will the madness ever stop?

“Aggressive Measures to Decrease “Door to Balloon” Time and Incidence of Unnecessary Cardiac Catheterization: Potential Risks and Role of Quality Improvement”

The Thermometer Accuracy Round-Up

Every patient gets vital signs.  They’re … vital, after all.  And the presence or absence of fever is one of those vital signs – and may substantially alter the diagnostic approach to a number of patients.

However, I’m guessing few of us universally use central sources of temperature measurement – bladder, rectal, pulmonary artery, or esophageal.  We, instead, rely on peripheral measurements – axillary, temporal artery, tympanic membrane, or oral.  And, these authors are here to tell us – within the bounds of their low-quality studies – we are being randomly misled.

This is a meta-analysis and systematic review of 75 studies comparing various peripheral temperature measurement techniques to central gold standard.  These authors rate ±0.5°C as a reasonable, clinically acceptable limit of agreement – and, frankly, even that seems like enough deviation to be relevant.

In their pooled analysis, however, peripheral thermometers were nowhere close – and the ranges worsened both with fever and hypothermia.  In adults, for fever the 95% limit of agreement ranged from -1.44°C to +1.46°C, and for hypothermia the range was -2.07°C to +1.90°C.  This led to a pooled sensitivity and specificity for fever of 64% and 96%.

The authors acknowledge multiple limitations to their data, mostly related to biases in sampling and measurement.  However, this probably still the best evidence available – and it seems it’s just about a flip of a coin whether a peripheral temperature measurement will miss a true fever.

“Accuracy of Peripheral Thermometers for Estimating Temperature”

The Macrolide Scourge, Updated

We’ve had a couple prior alerts regarding the potential cardiovascular risks of macrolides.  These have been taken with quite the grain of salt, particularly considering macrolides were, at one point, prescribed in a trial thought to be cardioprotective.

This meta-analysis is probably the most reasonable data to date on the subject.  These authors (of which there are 17) gather 33 studies comprising 20,779,963 participants.  These studies show, reasonably consistently, small increases in ventricular arrhythmias and sudden cardiac death.  The relative risks reported are 2.52 for VT and 1.31 for SCD, and there was not much reliable variation between different macrolide antibiotics.

However, these relative risks translate into just a handful of additional cases per million prescriptions.  The number needed to harm with cardiovascular death is about 25,000.  On the flip side, across the included studies, the all-cause mortality was unchanged.  So, yes, perhaps macrolides are not entirely benign – but neither is the underlying condition for which they are prescribed.

Overall, this study doesn’t add much to our insight into appropriate macrolide usage.  There may be particular subgroups for whom they may be best avoided, but, the alternative agent must be equally effective against the existing pathology – and not have its own particular undesired interaction.

Of course, if macrolides are used in context where their benefit is minimal or zero – then there is only harm.

“The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk”

The Great Reveal of Andexanet Alfa

The brave new world of “bleeding that doesn’t stop” is a little closer to ending today.  However, this is definitely just the smallest of baby steps in that direction – and hardly as straightforward and simple as the authors’ conclusion:
“Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.”
This is ANNEXA-A and ANNEXA-R, two healthy-volunteer studies evaluating the utility of Andexanet Alfa for reversal of Factor Xa inhibitors.  Andexanet is a recombinant Xa decoy protein with a higher afinity for the Xa inhibitors than endogenous Factor Xa, having the net effect of restoring thrombin production.  In these studies, the 40-odd participants in each were housed at the study site for 8 days, loaded with either apixaban or rivaroxaban, and then assigned in a 3:1 or 2:1 ratio to receive either Andexanet or placebo.  Then, the participants were assigned to single-bolus dosing or bolus plus infusion.

The general gist of the outcomes is best visualized by the following graphic:

Andexanet, as expected, rapidly binds circulating Factor Xa.  However, there are two quite obvious, clinically important considerations.  First, reversal is very short-acting if only the bolus is given.  Then, it seems clear while the Factor Xa inhibitor is bound, it cannot be eliminated – and there is a rebound phenomenon to near-baseline levels once the infusion is stopped.  It appears this may be a very tricky drug to use in certain clinical scenarios, considering the duration of required reversal – especially if full and permanent effects are desired.

And, as noted before, this is just baby steps.  This handful of healthy volunteers did not have any specific adverse events related to the infusion, but the small numbers prevent any reliable conclusions regarding safety.  This is also just a pharmacokinetic study without clinical outcomes, and we don’t truly know its real-world effectiveness based on this publication.

It is quite an interesting innovation, but it still lands somewhere between “promising” and “minimally useful” – and almost certainly expensive.

“Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”

It’s Not Time, It’s Brain

The evidence continues to mount that, simply, we’re doing it wrong.

Part of this is an acceptable confusion: we didn’t have the computational power or acquisition resolution capable of evaluating the intracranial circulation or perfusion when treating stroke.  However, as the evidence continues to mount from advanced imaging, it seems clear the “time” aspect is not the best determinant of outcome in stroke.

This is a small review of patients from DUST and MR CLEAN with MCA stroke and CT perfusion imaging available.  CTA is frequently performed to evaluate intracranial vasculature and estimate collateral circulation, but CT perfusion provides a dynamic look at contrast flow throughout the brain.

Based on this small 70 patient cohort, the reliability of the observations is hardly bulletproof, with wide 95% confidence intervals.  However, there is a reasonable, linear decrease in good outcomes as poor perfusion characteristics proliferate.  The best perfused collateral circulation led to 15 of 26 patients recovering to mRS 0-2.  While the flow rate and quality of the collaterals degraded, those with good recovery dropped to 12 of 26, then 1 of 12, and finally to 0 of 6.

The horizon is not far now where, hopefully, we’ll look back at the “time is brain” mantra as the infantile scramblings of the dark ages of acute stroke treatment.  Better imaging technology continues to demonstrate some brain is unrecoverable, regardless of timeframe, while others are likely excellent candidates for preservation of some function.  We ought to have much better options for tailoring treatment to the individual in the near future – and as this technology spreads.

“Impact of Collateral Status Evaluated by Dynamic Computed Tomographic Angiography on Clinical Outcome in Patients With Ischemic Stroke”