The Top “Overuse” of 2016

Another entry in JAMA Internal Medicine’s lovely “Less is More” series, this is a “systematic review” of the previous year’s literature regarding potentially unnecessary care. Living here in the asylum, it seems all our fellow inmates and I are consigned to issuing weather reports from the tempest – but, hey, baby steps.

Their “systematic review” is not particularly rigorous.  It’s basically a literature search, followed by a subjective distillation by author consensus to those considered to be the most potentially impactful – but, regardless, their list is worth reviewing. Without further ado, the highlights of their ten selections:

  • Transesophageal echocardiography is more informative than transthoracic in illuminating the etiology of a stroke, but the additive information does not have a clear downstream benefit on outcomes.
  • Patients undergoing computed tomography to rule out pulmonary embolism without algorithm-compliant use of D-dimer suffer from overuse and low-value testing.
  • CT use increased in all Emergency Department patients with respiratory symptoms, with no evidence of downstream change in prescribing, hospital admission, or mortality.
  • Supplemental oxygen does not demonstrate benefit in patients with chronic obstructive pulmonary disease and mild exertional hypoxia.
  • Small improvements in antibiotic prescribing were seen when comparisons to peers were performed.
  • A shared decision-making implementation for Emergency Department patients with chest pain increased patient engagement and demonstrated a secondary effect of diminished admission and cardiac testing.


“2017 Update on Medical Overuse: A Systematic Review”

Are We Killing People With 30-Day Readmission Targets?

Ever since the Center for Medicare and Medicaid Services announced their intention to penalize hospitals for early readmissions, folks have been worrying about the obvious consequences: would a focus on avoidance place patients at risk? Would patients best served in the hospital be pushed into other settings for suboptimal care?

That is the argument made in this short piece in the Journal of the American College of Cardiology. They look backwards at the last two decades of heart failure readmissions and short-term mortality, and take issue with the fundamental underlying premise of the quality measure, the inequities associated with the measure, and potential unintended harms. Their most illustrative example: when patients die outside the hospital within 30-days, paradoxically, they contribute to apparent improved performance in healthcare quality, as measured by 30-day readmission.

They back up their point by using the aggregate data analyzing readmissions between 2008 and 2014, published previously in JAMA, and focusing primarily on the heart failure component. In the original JAMA analysis, the evaluation paired individual hospital monthly readmission and risk-adjusted mortality, and were unable to identify an increased risk of death relating to reductions in 30-day readmissions. These authors say: too much tree, not enough forest. In the decade prior to announcements of 30-day readmission penalties, 30-day heart failure mortality had dropped 16.2%, but over the analysis period, 30-day heart failure mortality was back on the rise. In 2008 the 30-day mortality was 7.9% and by 2014 it was up to 9.2%, a 16.5% increase, and an even larger increase relative to the pre-study trend with decreasing mortality.

These are obviously two very different ways of looking at the same data, but the implication is fair: those charged with developing a quality measure should be able to conclusively demonstrate its effectiveness and safety. If any method of analysis raises concerns regarding the accepted balance of value and harm, the measure should be placed on a probationary status while rigorous re-evaluation proceeds.

“The Hospital Readmission Reduction Program Is Associated With Fewer Readmissions, More Deaths”

When Aggressive Sepsis Treatment Kills

Much has been made of efforts to detect and treat sepsis as early as possible after presentation, with many post-hoc analyses seeming to demonstrate time-sensitive mortality benefits associated with receiving the various components included in our “quality” measures. However, just like early goal-directed therapy back in the day, it has never truly become clear which element of early sepsis care confers the survival benefit. Absent specific data regarding how to best tailor therapy to the individual patient, we simply bludgeon everyone with the same sepsis bundle.

And, as we see here, that generalization is likely harmful.

This is a small randomized trial from Zambia – not to be confused with Nambia – in which 212 patients presenting with suspected infection, at least 2 systemic inflammatory response syndrome criteria, and hypotension were randomized to an early resuscitation protocol or “usual care”. The early resuscitation protocol sounds, generally speaking, similar to our modern approach to sepsis care – early intravenous fluid boluses with frequent intravascular volume assessment, vasopressors, and transfusions for severe anemia. The usual care cohort received, essentially, the same, only less so.

The two groups enrolled were roughly equivalent – but nothing like our sepsis cohort here in the United States. Approximately 90% of the patients enrolled were positive for the human immunodeficiency virus, half of the positive culture results were tuberculosis, the mean hemoglobin was 7.8 g/dL, and the majority of patients had been bedridden for over a week prior to presentation. Intravascular volume status and response to resuscitation was assessed by evaluating jugular venous pressure, tachypnea, and peripheral oxygenation. Finally, unlike many modern settings, most patients received dopamine as their vasopressor of choice and were admitted to general medical wards rather than intensive care units. In short, these are patients and care settings unlike in most industrial nations.

Mortality, not unexpectedly, was high – but it was much higher in those randomized to the early resuscitation cohort. Mortality in those receiving early resuscitation was 48.1%, compared with 33.0% in those receiving usual care. This mortality different then persisted out to 28 days, with over 60% mortality in the early resuscitation group at that time, compared with just over 40% in usual care.

This trial does not necessarily call into question the general principles of modern sepsis care, but it certainly provides a couple valuable lessons. The first, and most obvious, is the cautionary tale regarding generalizing research findings from one setting to another. Even a reasonably important, beneficial effect size can be transformed into a greater magnitude of harm if applied in another clinical setting. Then, this should clearly make us re-examine our current approach to sepsis care to ensure there is not a subgroup for whom early resuscitation is, in fact, the wrong answer. Our blind pursuit of checking boxes for quality measures, while generating an overall beneficial effect, is probably resulting in waste and harms for a substantial subgroup of those presenting with sepsis and septic shock.

“Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension”

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”

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”

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”

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”

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”

Blood Cultures Save Lives and Other Pearls of Wisdom

It’s been sixteen years since the introduction of Early Goal-Directed Therapy in the Emergency Department. For the past decade and a half, our lives have been turned upside-down by quality measures tied to the elements of this bundle. Remember when every patient with sepsis was mandated to receive a central line? How great were the costs – in real, in time, and in actual harms from these well-intentioned yet erroneous directives based off a single trial?

Regardless, thanks to the various follow-ups testing strict protocolization against the spectrum of timely recognition and aggressive intervention, we’ve come a long way. However, there are still mandates incorporating the vestiges of such elements of care –such as those introduced by the New York State Department of Health. Patients diagnosed with severe sepsis or septic shock are required to complete protocols consisting of 3-hour and 6-hour bundles including blood cultures, antibiotics, and intravenous fluids, among others.

This article, from the New England Journal, looks retrospectively at the mortality rates associated with completion of these various elements. Stratified by time-to-completion following initiation of the 3-hour bundle within 6 hours of arrival to the Emergency Department, these authors looked at the mortality associations of the bundle elements.

Winners: obtaining blood cultures, administering antibiotics, and measuring serum lactate
Losers: time to completion of a bolus of intravenous fluids

Of course, since blood cultures are obtained prior to antibiotic administration, these outcomes are co-linear – and they don’t actually save lives, as facetiously suggested in the post heading. But, antibiotic administration was associated with a fraction of a percent of increased mortality per hour delay over the first 12 hours after initiation of the bundle. Intravenous fluid administration, however, showed no apparent association with mortality.

These data are fraught with issues, of course, relating to their retrospective nature and the limitations of the underlying data collection. Their adjusted model accounts for a handful of features, but there are still potential confounders influencing mortality of those who received their bundle completion within 3 hours as compared to those who did not.  The differences in mortality, while a hard and important endpoint, are quite small.  Earlier is probably better, but the individual magnitude of benefit will be unevenly distributed around the average benefit, and while a delay of several hours might matter, minutes probably do not.  The authors are appropriately reserved with their conclusions, however, only stating these observational data support associations between mortality and antibiotic administration, and do not extend to any causal inferences.

The lack of an association between intravenous fluids and mortality, however, raises significant questions requiring further prospective investigation. Could it be, after these years wandering in the wilderness with such aggressive protocols, the only universally key feature is the initiation of appropriate antibiotics? Do our intravenous fluids, given without regard to individual patient factors, simply harm as many as they help, resulting in no net benefit?

These questions will need to be addressed in randomized controlled trials before the next level of evolution in our approach to sepsis, but the equipoise for such trials may now exist – to complete our journey from Early Goal-Directed to Source Control and Patient-Centered.  The difficulty will be, again, in pushing back against well-meaning but ill-conceived quality measures whose net effect on Emergency Department resource utilization may be harm, with only small benefits to a subset of critically ill patients with sepsis.

“Time to Treatment and Mortality during Mandated Emergency Care for Sepsis”

Correct, Endovascular Therapy Does Not Benefit All Patients

Unfortunately, that headline is the strongest takeaway available from these data.

Currently, endovascular therapy for stroke is recommended for all patients with a proximal arterial occlusion and can be treated within six hours. The much-ballyhooed “number needed to treat” for benefit is approximately five, and we have authors generating nonsensical literature with titles such as “Endovascular therapy for ischemic stroke: Save a minute—save a week” based on statistical calisthenics from this treatment effect.

But, anyone actually responsible for making decisions for these patients understands this is an average treatment effect. The profound improvements of a handful of patients with the most favorable treatment profiles obfuscate the limited benefit derived by the majority of those potentially eligible.

These authors have endeavored to apply a bit of precision medicine to the decision regarding endovascular intervention. Using ordinal logistic regression modeling, these authors used the MR CLEAN data to create a predictive model for good outcome (mRS score 0-2 at 90 days). These authors subsequently used the IMS-III data as their validation cohort. The final model displayed a C-statistic of 0.69 for the ordinal model and 0.73 for good functional outcome – which is to say, the output is closer to a coin flip than a informative prediction for use in clinical practice.

More importantly, however, is whether the substrate for the model is anachronistic, limiting its generalizability to modern practice. Beyond MR CLEAN, subsequent trials have demonstrated the importance of underlying tissue viability using either CT perfusion or MRI-based selection criteria when making treatment decisions. Their model is limited in its inclusion of just a measure of collateral circulation on angiogram, which is only a surrogate for potential tissue viability. Furthermore, the MR CLEAN cohort is comprised of only 500 patients, and the IMS-III validation only 260. This sample is far too small to properly develop a model for such a heterogenous set of patients as those presenting with proximal cerebrovascular occlusion. Finally, the choice of logistic regression can be debated, simply from a model standpoint, given its assumptions about underlying linear relationships in the data.

I appreciate the attempt to improve outcomes prediction for individual patients, particularly for a resource-intensive therapy such as endovascular intervention in stroke. Unfortunately, I feel the fundamental limitations of their model invalidate its clinical utility.

“Selection of patients for intra-arterial treatment for acute ischaemic stroke: development and validation of a clinical decision tool in two randomised trials”