IV Contrast, Unleashed

“The putative risk of administering modern intravenous iodinated contrast media in patients with reduced kidney function has been overstated.”

What a glorious lead sentence to the summary of this most recent guideline, a product of the American College of Radiology and the National Kidney Foundation. Historically, there has been great concern – including delay or exclusion of imaging – regarding the potential for acute kidney injury from intravenous contrast media in advanced imaging. However, a variety of recent different pieces of evidence have led to changes in perspective. This lovely guideline summarizes the data and issues a panoply of clarifications and recommendations regarding its use.

The most important distinction this guideline makes is between contrast-associated AKI and contrast-induced AKI. CA-AKI, as the authors note, is quite common – but is a rather a product of the underlying medical illness rather than the administration of IV contrast. CI-AKI, the attributable injury associated with IV contrast, is much harder to reliably observe. As noted in this article, summarizing mostly observational data sets, tweezing out the actual risk of harm from IV contrast media is challenging.

This guideline bundles together a whole list of concise questions and answers with regard to which patients may be at risk, the reliability of those estimates of risk, and what – if any – prophylaxis could be considered. Effectively – and the authors use many more words to clarify individual scenarios – the uncertainty regarding the safety of IV contrast begins to creep in around an eGFR of 30mL/Min/1.73m2. It should be noted this is related to a paucity of data, rather than a known observable risk. The authors recommendation, however, is not to exclude these patients from imaging, but rather to prompt a conversation between the referring professional and the radiologist to discuss the risks and benefits of IV contrast. Certainly life-threatening illnesses may require imaging, thus the careful weighing of risks versus benefits, and in these areas of uncertainly, additional cognitive consideration is reasonable.

With regard to prophylaxis against CI-AKI, the authors also make eminently reasonable statements saline volume expansion could be considered if clinically tolerated. The authors note this recommendation is based rather on observations of the utility of volume expansion for treating CA-AKI rather than CI-AKI, specifically, but likely represents a reasonable clinical practice.

In all, these guidelines quite nicely represent the uncertainly regarding harms from IV contrast administration, and, absent known harms from contrast, the potential harms from exclusion of IV contrast. As with most clinical problems, additional prospective research is critical to better inform practice.

“Use of Intravenous Iodinated Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation”
https://pubs.rsna.org/doi/10.1148/radiol.2019192094

Happy VITAMINS Day!

After a couple years wandering in the wilderness after the Marik report, and a few small or unrevealing trials, we finally have our first RCT evidence regarding the use of thiamine, vitamin C, and steroids in sepsis: the VITAMINS trial.

In this trial, 216 patients with septic shock received hydrocortisone 50mg every six hours, and were then randomized to usual care or open-label vitamin C 1.5g every six hours plus thiamine 200mg every twelve hours. The primary outcome was time alive and free of vasopressor administration up to day 7, along with pre-specified secondary mortality outcomes. Important exclusions in the eligibility screening process included onset of septic shock >24 hours, imminent death, and use of study drugs for other reasons. Few differences between the two groups were observed at baseline, although the control arm had median lactate level of 3.3 at enrollment compared with 4.2 in the intervention arm.

The primary outcome was: no different, 122.1 hours with the intervention and 124.6 hours in the control arm. The secondary mortality outcomes: at 28 days, no different, 22.6% vs. 20.4%; at 90 days, no different, 28.6% vs 24.5%. The remaining secondary outcomes, including ventilation-free days, renal replacement, and acute kidney injury were no different, but there was a small different in SOFA scores at day 3 favoring the intervention. The authors appropriately caution this observed improvement in SOFA score should be interpreted at your peril, as its significance is not adjusted for multiple comparisons and subject to both competing risks from early death and early discharge from the ICU.

So, the pure frequentist conclusion: this trial, repeated, would provide an estimate containing the true effect size with bounds crossing unity most of the time. The Bayesian conclusion, accounting for the weak, positive, prior evidence: there is a low probability of the true effect being positive. If you were holding off adopting the addition of thiamine and vitamin C, this trial reinforces your skepticism. If you’ve already adopted thiamine and vitamin C, it is unlikely harms were caused, but it is now more likely than not these treatments are not resulting in benefit. Additional trials will report results capable of further clarifying these observations.

The accompanying editorial by Andre Kalil sums up the interpretation of these results in context beautifully:

“Given that other studies are forthcoming, there appears to be no immediate justification for adoption of high-dose vitamin C, alone or in combination, as a component of treatment for sepsis. Moreover, use of high-dose vitamin C in combination or alone “just in case” or as a “measure of last resort,” aside from providing no survival benefits, could have several other potential consequences, including diverting funding from needed research to examine sepsis mechanisms and diagnostics; stifling the development of other sepsis therapies; perpetuating false hopes for patients, families, and clinicians; and delaying proven lifesaving therapies such as prompt initiation of antibiotic therapy.”

“Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock”
https://jamanetwork.com/journals/jama/fullarticle/2759414

Tamiflu, Cure-All

Once upon a time in Europe, we find they are beset by a befuddling problem: no one uses oseltamivir.

“Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials.”

Ah, to have such problems.

These authors choose to address this dire problem in the most pragmatic fashion possible: rather than try to determine a subgroup of potential maximal benefit, just blindly give everyone oseltamivir in empiric fashion for influenza-like illness. It’s not what one would consider “high-value care”, but it certainly effectively eliminates the barriers to prescribing.

In this open-label trial, patients presenting with influenza-like illness to primary care were assigned to “usual care” or “usual care plus oseltamivir”. Across three influenza seasons, the authors recruited 3,266 participants across 15 countries in Europe. The outcomes were universally excellent: oseltamivir use decreased time to symptom resolution a mean of 1.02 days, effectively reducing mean suffering from 6.73 days to 5.71 days.

And, the better news, oseltamivir worked whether you had influenza or not – half the patients in the trial had confirmed influenza infection while half did not, and the hazard ratio for benefit was actually better [ed. not significantly so] in those who did not have influenza.

… and thus invalidates the entire trial as a giant placebo effect. The industry-funded authors of the most recent meta-analysis of industry-funded trials for the approval of oseltamivir said it best, after all:

“In the intention-to-treat-not infected population, the estimated time ratio was close to unity (time ratio 0·99, 95% CI 0·88–1·12; p=0·91), so only participants identified as influenza-infected benefited from oseltamivir.”

This trial does not show benefit to liberal oseltamivir use. There is no new indication hereby discovered regarding oseltamivir’s efficacy for non-influenza influenza-like viral illness – it simply shows people feel better when they get medicine (particularly when it is more expensive).

“Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/31839279

The Clinical Impact of SAH Decision Rules

The Ottawa Subarachnoid Hemorrhage Rule has been around a long time now, dating back to 2013. The “six hour CT” rule has been around even longer, dating back even to 2011. They’ve become entwined in at least the discussion around the evaluation of SAH, if not clinical practice.

… but are they actually useful?

This is the “before and after” study from Perry and Stiell (not to be confused with Penn and Teller), in which the practice of Canadian physicians was examined around the time these rules were under development and in publication. These authors gathered data on patients presenting with atraumatic headache spanning the time period between 2011 and 2016, looking at resource utilization and missed SAH before and after adoption of both the Ottawa SAH Rule and the 6-hour CT Rule. Specifically, practicing clinicians were instructed not to use decision rules for the basis of patient care until June 2013, at which point clinicians were actively encouraged to do so.

The basic findings:

  • The Ottawa SAH Rule doesn’t change much.
  • The 6-hour CT Rule probably reduces downstream lumbar puncture/CTA.

Again, with concern for generalizability, a full 5.1% of their qualifying atraumatic headaches were diagnosed with SAH across the study period. The rate of investigation of these patients remained high, about 88%, regardless of study period – and regardless whether the Ottawa Rule criteria were met. However, for patients presenting within 6 hours of headache onset, the rate of subsequent LP dropped from 31.3% to 15.1%. The Ottawa SAH Rule showed its expected specificity of about 12%, and, therefore, was 100% sensitive. The 6-hour CT Rule “missed” 5 of 111 patients, however, for various reasons – one radiology misread, a false-positive owing to profound anemia, a non-aneurysmal SAH from dural vein fistula, and two cases of false-positive LPs meeting their study criteria for false-negative CT.

A long story made short, 1) keep using the 6-hour CT rule with the caveat of known potential confounders to visible blood (anemia); 2) the Ottawa Rule is only clinical useful as a one-way decision instrument owing to its poor positive likelihood ratio.

“Prospective Implementation of the Ottawa Subarachnoid Hemorrhage Rule and 6-Hour Computed Tomography Rule”

https://www.ncbi.nlm.nih.gov/pubmed/31805846

Sepsis Alerts Save Lives!

Not doctors, of course – the alerts.

This is one of those “we had to do it, so we studied it” sorts of evaluations because, as most of us have experienced, the decision to implement the sepsis alerts is not always driven by pent-up clinician demand.

The authors describe this as sort of “natural experiment”, where a phased or stepped roll-out allows for some presumption of control for unmeasured cultural and process confounders limiting pre-/post- studies. In this case, the decision was made to implement the “St John Sepsis Algorithm” developed by Cerner. This algorithm is composed of two alerts – one somewhat SIRS- or inflammation-based for “suspicion of sepsis”, and one with organ dysfunction for “suspicion of severe sepsis”. The “phased” part of the roll-out involved turning on the alerts first in the acute inpatient wards, then the Emergency Department, and then the specialty wards. Prior to being activated, however, the alert algorithm ran “silently” to create the comparison group of those for whom an alert would have been triggered.

The short summary:

  • In their inpatient wards, mortality among patients meeting alert criteria decreased from 6.4% to 5.1%.
  • In their Emergency Department, admitted patients meeting alert criteria were less likely to have a ≥7 day inpatient length-of-stay.
  • In their Emergency Departments, antibiotic administration of patients meeting alert criteria within 1 hour of the alert firing increased from 36.9% to 44.7%.

There are major problems here, of course, both intrinsic to their study design and otherwise. While it is a “multisite” study, there are only two hospitals involved. The “phased” implementation not the typical different-hospitals-at-different-times, but within each hospital. They report inpatient mortality changes without actually reporting any changes in clinician behavior between the pre- and post- phases, i.e., what did clinicians actually do in response to the alerts? Then, they look at timely antibiotic administration, but they do not look at general antibiotic volume or the various unintended consequences potentially associated with this alert. Did admission rates increase? Did percentages of discharged patients receiving intravenous antibiotics increase? Did clostridium difficle infection rates increase?

Absent the funding and infrastructure to better prospectively study these sorts of interventions, these “natural experiments” can be useful evidence. However, these authors do not seem to have taken an expansive enough view of their data with which to fully support an unquestioned conclusion of benefit to the alert intervention.

“Evaluating a digital sepsis alert in a London multisite hospital network: a natural experiment using electronic health record data”

https://academic.oup.com/jamia/advance-article/doi/10.1093/jamia/ocz186/5607431

YEARS, But Wells

It’s the Monday after Thanksgiving, so it’s time to turn the brains back on – and notice an oddly robust cultivation of articles worthy of comment dropped just before the holiday. This is the first, the “Pulmonary Embolism Graduated D-Dimer” (PEGeD) study, a rather obtuse name for what is effectively a pretest likelihood-adjusted implementation of D-dimer. This is also, effectively, what was done with the YEARS protocol – so, what’s new?

In this iteration of the concept, the authors use the Wells score, stratifying patients to either low, moderate, or high probability. A few published work-up algorithms describe pathways of care in which low probability leads to PERC, while the higher-risk cohort undergoes D-dimer testing or directly to CTPA to rule out PE. In this algorithm, those with “low” probability still undergo D-dimer testing – but with a cut-off threshold of 1000 ng/mL warranting advanced imaging. The primary outcome was symptomatic, objectively-verified venous thromboembolism, including PE and deep venous thrombosis, at 90 days.

These authors enrolled a cohort of 2,017 patients between 2015 and 2018, with 1,752 in the “low” probability cohort, 218 “moderate”, and 47 “high”. Overall prevalence of PE on initial testing was 7% and advanced imaging was performed on 34%, for an imaging yield of 24%. The general finding of most importance to the practicing clinician is their observation that 1,285 low-risk patients had D-dimer <1000 ng/mL and 40 moderate-risk patients had D-dimer <500 ng/mL and none had VTE detected at 90 day follow-up. Helpfully, these authors even compare their yield directly to the YEARS protocol – and find about 40 fewer patients would have undergone imaging with PEGeD than YEARS, which makes it basically a wash. They also compare their strategy to an age-adjusted D-dimer, which is a bit odd, considering they are not competing strategies, but synergistic.

The idea of pretest-adjusted D-dimer has been around a very long time, dating back to at least 2012. There’s nothing magical about a cut-off of 1000 ng/mL other than Round Numbers, but it is a serendipitously reasonable starting point for this approach. The real elephant in the room, however, is there were only 87 PEs in their low-risk cohort, for a prevalence of 4.9%. This may yet even over-represent the prevalence of PE in community practice in certain settings (read: the United States). Considering the accepted miss rate for PE is considered to be at least 1%, owing to the likelihood of false-positives and harms from anticoagulation, it is likely an even more aggressive cut-off or imaging-elimination strategy should be pursued.

However, I certainly do not want to minimize this work – adding good, prospective data pushing imaging stewardship is of great importance, whatever minor shortcomings might be observed. At the very least, please considering using PEGeD or YEARS as the basis for your imaging algorithm – and add age-adjusted D-dimer on top for even better reductions in unnecessary imaging.

“Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability”
https://www.nejm.org/doi/full/10.1056/NEJMoa1909159

Does My Patient Have Prion Disease?

No, they don’t.

But, they might.

Between the years of 2003 and 2015, the National Prion Disease Pathology Surveillance Center captured 5,212 deaths due to prion disease in the United States. This number is clearly greater than zero, but the average annual incidence is around 1.2 cases per million population.

Not the most profound impact on your practice in the Emergency Department, but just one more element of curiosity to file away as trivia.

“Prion disease incidence in the United States, 2003-2015.”
https://www.ncbi.nlm.nih.gov/pubmed/31757870

Steroids for Severe Influenza?

There’s a little bit of evidence supporting the use of corticosteroids in both severe sepsis and in severe pneumonia. Severe influenza is both of these things, yet neither. Should we try corticosteroids?

Many have – but, unfortunately, few have rigorously evaluated it. This systematic review found 30 eligible studies, all of which were observational excepting one randomized trial. From this poor-quality data, associations between steroid use and increased mortality and increased hospital-acquired infection were observed. While this hardly excludes a potential benefit to steroids in selected cases of severe influenza, it certainly ought to encourage you to defer use of steroids until high-quality data supports the practice, if ever.

“Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis.”
https://www.ncbi.nlm.nih.gov/pubmed/31743228

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

The Non-Invasive Testing for Chest Pain Half-Truth

The utility or disutility of non-invasive diagnostic testing for chest pain – CT coronary angiograms, treadmill stress testing, myocardial perfusion imaging and the like – in the Emergency Department remains controversial. A couple days ago, the daily ACEP News Bulletin e-mail referenced an article regarding non-invasive testing featuring the following statement:

“Patients who underwent noninvasive diagnostic testing after evaluation for chest pain in the” emergency department (ED) appeared to have “a lower observed rate of CV death or MI,” researchers concluded.

While this statement is not strictly untrue, it is dramatically clarified by including the next sentence from the authors’ own abstract conclusion:

“This lower rate was driven by the high-risk subgroup.”

The study cited is a propensity-matched cohort of 370,863 patients discharged from the ED after a visit for chest pain in Ontario, Canada. They created matched cohorts featuring 96,457 patients who each either underwent non-invasive cardiac testing in the Emergency Department or did not. Interestingly enough, at 90 days, those who underwent testing had a higher risk of their combined endpoint of cardiovascular death or myocardial infarction. However, by 1 year, the rate of the combined endpoint in those who underwent testing had dropped below the rate for those who did not. The hazard difference was small, however, and driven by small absolute differences in outcomes for those in the high-risk and intermediate-risk cohorts.

Rather than try and read into this study some general advantage to non-invasive testing in the Emergency Department, it would only imply testing of value would be for those who are at intermediate- or high-risk for adverse cardiovascular outcomes. Next, it also does not specifically mandate or imply the testing should be done in the ED or, based on the 90 day outcomes data, even urgently upon discharge. Finally, the newsworthy snippet also does not mention dramatic increases in downstream invasive angiography, PCI, and cardiology visits associated with those in those who underwent non-invasive testing.

The ultimate conclusion is not practice changing in the least: appropriately selected patients may be candidates for the appropriately selected test. Individualized decisions need to be made for those at intermediate- and high-risk for cardiovascular outcomes. Likewise, the relative urgency of testing ought to be determined on an individual basis – and not routinely in the ED. This is, in fact, the authors’ own conclusion – just not well-reflected by the ACEP News Bulletin.

“Clinical Effectiveness of Cardiac Noninvasive Diagnostic Testing in
Patients Discharged From the Emergency Department for Chest Pain”
https://www.ahajournals.org/doi/10.1161/JAHA.119.013824