An Oddly Dire Look at CIN after CTPA

This is an abstract that sucked me in – not because of the concept of the study – but because of its quoted incidence of adverse outcomes.  23.7% incidence of contrast-induced nephropathy following a CT pulmonary angiogram!  12.5% incidence of renal failure!  12.8% in-hospital mortality!

But, no.

The study itself is a comparison between three different prophylaxis methods for the prevention of CIN after CTPA – N-acetylcysteine plus normal saline, bicarbonate plus NS, or NS alone.  The simple summary: no difference between groups.

But, getting back to those dire numbers – roughly double the typically reported incidence of CIN.  They’re a mirage.  In reality, they assigned the primary outcome to all 26 (9.3%) of patients lost to follow-up.  Therefore, the starting point for their outcomes of interest are in a more reasonable range: 15.2% CIN, 2.6% renal failure, and 3.0% in-hospital mortality.

This, again, leads us back to the question: how much renal impairment is attributable to the CTPA, and how much to the underlying disease processes leading patients to require a CTPA in the first place?  Yield for PE on their CTPA cohort was 31.9%, which, in itself, elevates the comorbid burden of the population and could contribute to heart failure and renal injury.  There is no control group not receiving CTPA – for obvious clinical reasons – so it is hard to estimate the additive injury resulting directly from the CTPA.

But, at least, the big numbers displayed in their abstract a little misleading.

“The high risk of contrast induced nephropathy in patients with suspected pulmonary embolism despite three different prophylaxis: A randomized controlled trial”

Next Up in Syncope Prediction

The Great White North is the land of clinical decision instruments.  Canadian Head, Canadian C-Spine, Ottawa Ankle, Ottawa SAH, the list goes on – and now, from the same esteemed group: the Canadian Syncope Risk Score.

The vast majority of patients with syncope have unrevealing initial and, if admitted, in-house evaluation.  That said, any physiologic interruptions in the ability to perfuse the brain portend a poor prognosis greater than the general background radiation.  These authors performed an observational study over the course of four years to prospectively derive a decision instrument to support risk-stratification for syncope.

There were 4,030 patients enrolled and eligible for analysis based on 30-day follow-up, and 147 of these suffered a “serious adverse event”.  They identified 43 candidate predictors for prospective collection, and ultimately this resulted in a multivariate logistic regression predictive model with 9 elements.  Scores range from -3, with a 0.4% estimated risk for SAE, to 11, with an 83.6% estimated risk for SAE.  Useable confidence intervals, however, were mostly scores <5.

There are a few things I would quibble with regarding this study.  The “serious adverse event” definition is rather broad, and includes 30-day events for which the underlying pathology was not present or necessarily preventable at the initial visit.  For example, a patient with a subsequent encounter for a GI bleed or a case of appendicitis fit their criteria of SAE.  This would diminish the instrument’s apparent sensitivity without materially improving its clinical relevance.  Then, there is the oddity of incorporating the final ED diagnosis into the scoring system – where a provisional diagnosis of “vasovagal syncope” is -2, and a diagnosis of “cardiac syncope” is +2.  The authors explicitly defend its inclusion and the methods behind it – but I feel its subjectivity coupled with widespread practice variation will impair this rule’s generalizability and external validation.

Finally, the last issue with these sorts of “rules”: “high risk” is frequently conflated to mean “admit to hospital”.  In many situations close to the end-of-life, the protective effect of hospitalization and medical intervention vanishes – and may have little or no value.  This sort of stratification should be applied within the appropriate medical and social context, rather than simply triggering admission.

“Development of the Canadian Syncope Risk Score to predict serious adverse events after emergency department assessment of syncope”

Perpetuating the Flawed Approach to Chest Pain

Everyone has their favored chest pain accelerated diagnostic risk-stratification algorithm or pathway these days.  TIMI, HEART, ADAPT, MACS, Vancouver, EDACS – the list goes on and on.  What has become painfully clear from this latest article, however, is this approach is fundamentally flawed.

This is a prospective effectiveness trial comparing ADAPT to EDACS in the New Zealand population.  Each “chest pain rule-out” was randomized to either the ADAPT pathway – using modified TIMI, ECG, and 0- and 2-hour troponins – or the EDACS pathway – which is its own unique scoring system, ECG, and 0- and 2-hour troponins.  The ADAPT pathway classified 30.8% of these patients as “low risk”, while the EDACS classified 41.6% as such.  Despite this, their primary outcome – patients discharged from the ED within 6 hours – non-significantly favored the ADAPT group, 34.4% vs 32.3%.

To me, this represents a few things.

We are still have an irrational, cultural fear of chest pain.  Only 11.6% of their total cohort had STEMI or NSTEMI, and another 5.7% received a diagnosis of “unstable angina”.  Thus, potentially greater than 50% of patients were still hospitalized unnecessarily.  Furthermore, this cultural fear of chest pain was strong enough to prevent acceptance of the more-aggressive EDACS decision instrument being tested in this study.  A full 15% of low-risk patients by the EDACS instrument failed to be discharged within 6 hours, despite their evaluation being complete following 2-hour troponin testing.

But, even these observations are a digression from the core hypothesis: ADPs are a flawed approach.  Poor outcomes are such the rarity, and so difficult to predict, that our thought process ought be predicated on a foundation that most patients will do well, regardless, and only the highest-risk should stay in the hospital.  Our decision-making should probably be broken down into three steps:

  • Does this patient have STEMI/NSTEMI/true UA?  This is the domain of inquiry into high-sensitivity troponin assays.
  • Does the patient need any provocative testing at all?  I.e., the “No Objective Testing Rule”.
  • Finally, are there “red flag” clinical features that preclude outpatient provocative testing?  The handful of patients with concerning EKG changes, crescendo symptoms, or other high-risk factors fall into this category.

If we are doing chest pain close to correctly, the numbers from this article would be flipped – rather than ~30% being discharged, we ought to be ~70%.

“Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice”

The “IV Antibiotics” Sham

Among the many overused tropes in medicine is the myth of the supremacy of intravenous antibiotics.  In the appropriate clinical context, it’s just a waste.

This is a retrospective analysis of 36,405 patients hospitalized for community-acquired pneumonia, and for whom a fluoroquinolone was selected as therapy.  The vast majority – 94% – received an intravenous dose, while the remaining 2,205 (6%) were treated orally.  Unadjusted mortality favored the oral dose – unsurprisingly, as those patients also generally has fewer comorbid conditions.  In their multivariate, propensity-matched analysis, there was no difference in mortality, intensive care unit escalation, or mechanical ventilation.

These results are wholly unsurprising, and the key feature is the class of antibiotic involved.  Commonly used antibiotics in the fluoroquinolone class, trimethoprim-sulfamethoxazole, metronidazole, and clindamycin, among others, have excellent oral absorption.  I have seen many a referral to the Emergency Department for “intravenous antibiotics” prior to an anticipated discharge to home therapy when any one of these choices could have obviated the entire encounter.

“Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired Pneumonia”

The Magic Bacterial Divining Rod

Antibiotic overuse is a real issue.  In modern countries, despite obsessing over antibiotic stewardship, we are still suckers for the excessive use of both narrow-spectrum antibiotics for ambulatory patients and broad-spectrum antibiotics for the critically ill.  In less resource-capable areas, the tests used to stratify patients as potentially bacterial or viral exceed the cost of the antibiotics – also leading down the path to overuse.

This breathless coverage, featured in Time, the AFP, and proudly advertised by Stanford Medicine, profiles a new panel of tests that is destined to bring clarity.  Rather than relying simply on a single biomarker, “our test can detect an infection anywhere in the body by ‘reading the immune system’”.

They used retrospective genetic expression cohorts from children and adults with supposedly confirmed non-infectious or infectious etiologies to derive and validate a scoring system to differentiate the underlying cause of sepsis.  They then further trim their model by eliminating infants and predominately healthy patients from outpatient cohorts.  Ultimately, they then test their model on a previously uncharacterized whole blood sample from 96 pediatric sepsis patients and report an AUC for viral vs. bacterial sepsis of 0.84, with a -LR of 0.15 and +LR of 3.0 for bacterial infections.  At face value, translated to a presumed clinical setting with a generally low prevalence of bacterial infection complicating SIRS, this is an uninspiring result.

However, these authors rather focus their discussion and press releases around the -LR of 0.10 and +LR of 2.34 produced as part of their ideal validation cohort, trumpeting its superiority over the -LR for procalcitonin of 0.29 as “three-fold improvement”.  This is, of course, nonsense, as the AUC from that same procalcitonin meta-analysis was 0.85, and these authors are simply cherry-picking one threshold and performance characteristic for their comparison.

Now, that’s hardly to say this is not novel work, and their confusion matrices showing clustering of non-infected SIRS vs. bacterial sepsis vs. viral sepsis are quite lovely.  Their approach is interesting, and very well could ultimately outperform existing strategies.  However, their current performance clearly does not match the hype, and they are miles away from a meaningful validation.  Furthermore, the sort of nano-array assay required is neither fast enough to be clinically useful nor likely to be produced cheaply enough to be used in some of the resource-poor settings they claim to be addressing.

It makes for a nice headline, but it’s better consigned to the “Fantasy/Science Fiction” shelf of your local bookstore for now.

“Robust classification of bacterial and viral infections via integrated host gene expression diagnostics”

Pan-Scans Don’t Save Lives

Humans are fallible.  We don’t always make good choices, and our patients – bless their hearts – can sometimes be time bombs wrapped in meat.  Logically, then, as many trauma services have concluded, the solution is to eliminate the weak link: don’t let the human chose which parts of the body to scan – just scan it all.

This is REACT-2, a randomised [sic] trial evaluating precisely the limits to human judgment in a resource-utilization versus immediacy context.  In this multi-center trial, adult trauma patients wth suspected serious injury were randomized to either imaging guided by clinical evaluation or total-body CT.  The primary outcome was in-hospital mortality, with secondary outcomes relating to timeliness of diagnosis, to mortality in other time frames, morbidity, and costs.

This was a massive undertaking, with 1,403 patients randomly assigned to one of the arms, with ~540 in each arm successfully allocated and included in their primary analysis.  Each cohort was well-matched on baseline characteristics, including all physiologic markers, although the Triage Revised Trauma Score was slightly lower (worse) for the total-body CT group.  The results, in most concise form, weakly favor selective scanning.  There was no difference in mortality nor complications nor length-of-stay nor virtually any reliable secondary outcome.  Costs, as measured in European terms, were no different, despite the few scans obviated.  Time-to-diagnosis was slightly faster in the total-body CT group, owing to skipping initial conventional radiography, while radiation exposure was slightly lower in the selective scanning group.

In some respects, it is not surprising there were no differences found – as CT was still frequently utilized in the selective CT cohort, including nearly half that ultimately underwent total-body CT.  There were some differences noted in in-hospital Injury Severity Score between groups, and I agree with Rory Spiegel’s assertion this is probably an artifact of the routine total-body CT.  This study can be used to justify either strategy, however – with selective CT proponents focusing on the lack of differences in patient-oriented outcomes, and total-body CT proponents noting minimal resource and radiation savings at the expense of timeliness.

“Immediate total-body CT scanning versus conventional imaging and selective CT scanning in patients with severe trauma (REACT-2): a randomised controlled trial”

The tPA Pushback Begins

It isn’t news to anyone in the Emergency Medicine community that tPA isn’t as effective as its efficacy trials suggested, and its overuse is driven by “quality” measures and medicolegal concerns more than any true belief in its usefulness.  However, it remains rare in the Neurology literature to challenge the primacy of tPA – it is much more frequent to see articles promoting and/or defending its expanded use.

This small retrospective series looks at a registry of stroke patients eligible for alteplase who received a CT perfusion study as part of their initial evaluation.  As criteria for review, the CT perfusion lesion needed to be <15mL in calculated volume.  Their final cohort included 366 patients with mostly mild-to-moderate strokes (NIHSS median 8 in each), and a little over half were treated with alteplase, while the remainder were not.  As a retrospective and confounded study, the level of evidence is weak, but the untreated population had significantly better outcomes (mRS 0-1 in 57% vs. 69%), and avoided such complications as parenchymal hemorrhage.

The authors conclude:

“we suggest that neither CTA nor standard clinical/NCCT assessment can appropriately define a relatively large sub-group of patients who are clinically eligible for alteplase, yet appear to have no benefit from treatment.”

Yes, if the volume of acutely injured tissue is quite small, the potential benefit of any therapy has an obvious ceiling – even before considering the viability of the affected tissue or the potential effectiveness of reperfusion.  But the key point here is one I’ve made, most recently at #smaccDUB: we can better individualize care, and avoid costs and risks, with more information.

Thanks to Robert Goulden for sending this in!

“Too good to treat? Ischemic stroke patients with small CT perfusion lesions may not benefit from thrombolysis”

The Sweetest Emergency Department Discharge

When the writers of television drama imagine the Emergency Department, they imagine – you know – emergencies.  Life, death, gray areas in between, and the drama of the critically ill.  People with – you know – symptoms.

Now, our Emergency Departments fill up with the asymptomatic – hypertension and hyperglycemia.  Silent killers, to be sure, but on geologic time scales compared to the attention span of the average Emergency Physician.  As we covered last week, asymptomatic hypertension is nearly always an inappropriate Emergency Department referral.  Now, just the same, we see the same strains of futile pedaling in hyperglycemia.

This is a retrospective, single-center evaluation of all patients arriving with a glucose level ≥400 mg/dL and subsequently discharged.  Patient admission and discharge glucose level were measured, any testing and treatment recorded, and each was followed-up specifically for healthcare encounters and hospitalizations within seven days.  All told, they identified 422 patients and 566 ED encounters for chart review.

In their cohort, the median arrival and discharge glucose levels were 491 mg/dL and 334 mg/dL.  Treatment and testing varied wildly, with most receiving some sort of chemistry or urine testing, most receiving some intravenous fluid, and the majority receiving some subcutaneous insulin.  Fabulously, 11 patients were even discharged (most AMA) with glucose beyond the range of the point-of-care machine (600 mg/dL).  Nearly everyone in their cohort for whom they were able to follow-up did well: only 25 (4%) were hospitalized on a re-visit within 7 days, and only two did so for a glucose-metabolism complications, both diabetic ketoacidosis.  The reasonable conclusion of these authors: “attaining a specific glucose-level goal before discharge in patients with moderate to severe hyperglycemia may be less important than traditionally thought.”

This study does not review the downstream resource utilization and outcomes for those admitted on their initial visit.  A comparison with an admitted versus discharged cohort might have given some representation of benefit derived from intensive treatment and re-education, although, the surrogate and patient-oriented complications relating to poor glucose control are infrequent and generally long-term complications.  Furthermore, patients with poor glucose control are not always those for whom an inpatient hospitalization resolves the issues relating to their future poor glucose control.

These patients are still a challenge to manage appropriately.  The role of the Emergency Department is in ruling out treatable pathology or complications of sustained hyperglycemic or insulin-deficient states.  Unlike hypertension, a little more work is usually indicated for these patients.  The ED evaluation is the easy part; finding ways to keep these patients healthy long term is the larger question.

“Discharge Glucose Is Not Associated With Short-Term Adverse Outcomes in Emergency Department Patients With Moderate to Severe Hyperglycemia”

Still Meandering Towards Apneic Oxygenation

The use of apneic oxygenation – so-called NODESAT – has been gaining rapidly in popularity.  Curiously enough, however, its continued promotion occurs in the absence of high-quality evidence for benefit.

This most recent study is a prospective, observational evaluation of two years’ worth of intubation procedural outcomes.  Patients receiving passive oxygenation during intubation were compared with those who did not, with the primary outcome being hypoxia (O2 saturation <90%) on the first-pass of intubation.  During this time period, the use of apneic oxygenation was explicitly encouraged as a quality improvement initiative.  Of the 1,140 intubations during this time period, 635 patients were included for analysis; 380 utilized apneic oxygenation and 255 did not.  The apneic oxygenation cohort had a 17.9% incidence of hypoxia on the first intubation attempt, compared with 31.0% without.  The authors conclude their observational data favors apnea oxygenation, and may improve safety.

This is a reasonable conclusion, to be certain.  There were, of course, massive confounders regarding the two cohorts – and the largest predictor of hypoxia was not apneic oxygenation or technical factors, but simply whether the baseline oxygen saturation was >93%.  An observational study, particularly one excluding 20% of potentially eligible patients due to incomplete data, simply continues to serve as hypothesis-generating for definitive evaluation.

I am not opposed to the use of apneic oxygenation, but it is reasonable to be realistic about the underlying evidence and not to behave dogmatically regarding its use.  There are probably a few acute procedural delays associated with its use, but any patient-oriented harms or benefits would seem to be rather difficult to detect.

Other notes:

  • LITFL publishes a lovely synopsis on the topic here.
  • Yes, I’m about four months late to the party on this article – having missed the electronic publication back in February!

“First Pass Success Without Hypoxemia Is Increased With the Use of Apneic Oxygenation During Rapid Sequence Intubation in the Emergency Department”

You Can’t Spell “Insanity” Without tPA

When you think you’ve seen it all – a call to administer tPA to acute stroke patients without a prior non-contrast CT.

Indeed, in this “Views & Reviews” article, the authors ask explicitly the question: “Is the administration of alteplase to patients with primary ICH that harmful?”  After much stimulating confabulation, the authors bafflingly conclude: “we cannot argue with confidence that alteplase administration to patients with ICH is harmful”.

Perhaps they’ve never treated patients with alteplase personally, and they further mis-cite or misinterpret the evidence regarding the influence of cerebral microbleeds on symptomatic intracranial hemorrhage.  Despite the clear evidence from multiple meta-analyses that cerebral microbleed burden prior to alteplase administration leads to substantially increased risk of ICH and neurologic worsening, these authors sum up this evidence as “either no increased risk of symptomatic ICH or an increased risk that does not necessarily preclude an overall benefit from alteplase.”


Even better, the entire purpose of their intellectual exercise boils down to discarding the inconvenience of pre-lytic CT so that alteplase can be delivered pre-hospital.  Yes, rather than clinically correlating the presentation with maximal vascular and perfusion information to consider the safest, most potentially effective (if any) reperfusion therapy – these authors are promoting administration of a $6000 medication in a pre-hospital setting with a paucity of diagnostic expertise or technology available.

Good plan.

“And why not thrombolysis in the ambulance (at least for some)?”