Stayin’ Alive Below 65

Just a quick note looking at this lovely trial hypotension trial, evaluating potential use of lower mean arterial pressure targets in elderly patients receiving vasopressors.

Quick summary: Less is more. With a primary outcome of 90-day mortality, outcomes were no worse in patients randomized to a MAP target of 60-65 mmHg rather than “usual care” (≥65 mmHg) – 41.0% vs. 43.8% (-2.85%, 95%CI -6.75 to 1.05). Stated in formal terms, however, the trial failed to demonstrate a statistically significant difference between the treatment arms, and the confidence interval crosses unity. That said, I certainly agree with the accompanying editorial – it should be considered likely there is a potential advantage to “permitting” hypotension, rather than being hedging against intermittent dips. This trial wouldn’t go so far as to say the 65 mmHg is not the MAP target – patients in the “permissive” cohort still had a mean MAP on vasopressors of 66.7 mmHg, while those in the usual care arm trended higher at 72.6 mmHg – but, additional work looking at lower targets is reasonable.

There are, of course, minor oddities to be observed when considering how (or if) to generalize these data. While 78% of patients received norepinephrine, the second-most popular vasopressor was metaraminol, a predominately alpha agonist, used in almost a third of those randomized. Interestingly, fewer than half the patients enrolled were in “septic shock” by Sepsis-3 definitions, while only another quarter were noted to have “sepsis (not in shock)”. Finally, while the findings are generally consistent across all age cohorts, the mean age is ~75, and nearly 75% of those screened were excluded for one of many reasons.

This study is a lovely demonstration of a rather straightforward underlying principle – MAP is not a measure of tissue perfusion, and is used rather as a surrogate for the ultimately-important microvascular circulation. Making big tubes run at a higher pressure at the expense of clamping down little tubes may be harmful – hence the rationale for this trial, and future ones.

As another random aside, I might make a note here for aspiring researchers – the guidelines will frequently tell you where knowledge gaps exist. The 2012 Surviving Sepsis guidelines gave the MAP >65 target a “1C” recommendation, with “1” meaning consensus for the recommendation was strong, but “C” meaning the evidence was weak. Looking at guideline recommendations and their accompanying level of evidence provides: 1) clues as to which clinical questions are important enough to be addressed by guidelines, and 2) the gaps in the evidence. Guideline authors will even, frequently, explicitly call out certain clinical questions for further study. I wouldn’t go so far as to call it a roadmap to clarifying the important questions in your specialty, but it certainly could be fertile.

“Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension”
https://jamanetwork.com/journals/jama/fullarticle/2761427

Put an End to Routine Chest Tubes

If you’ve watched any television or cinema, you’ve probably seen a violent encounter or two leading to a puncture wound to the chest. The affected party is usually worse for the wear. The suffering is real.

So, if there were a way – if you suffered a pneumothorax – to forgo such an invasion of the thoracic cavity, would you? The U.S. and European guidelines regarding the necessity of such a procedure are not in agreement, and include both chest tube placement and aspiration as options. However, neither explore another option – no intervention. Now, that paradigm may be dramatically altered.

This is a rather simple trial: spontaneous pneumothorax of moderate-to-large (32% or greater, by the Collins method) would be randomized to intervention or conservative management. By intervention, patients would undergo placement of a small-bore chest tube with subsequent observation and discharge or hospital admission as necessary. By conservative, patients were observed in the Emergency Department and discharged unless worsening as defined in the study protocol. The primary outcome was full lung expansion 8 weeks after randomization, with a non-inferiority margin of -9% percentage points.

There were 316 patients randomized, and 25 of the 162 randomized to the conservative management arm underwent an intervention owing to worsening symptoms during initial observation. The remaining cases represented those assessed for outcomes at 8 weeks.

Short story: Success – full expansion in 98.5% with intervention and 94.4% with conservative management.

Long story: If patients with missing data after 56 days were imputed as treatment failures, because more of those in the conservative management arm were lost to follow-up, these data are potentially fallible.

So, this clearly indicates conservative management is probably the preferred course, recognizing a significant number will require an intervention due to early progression. The risk difference is uncertain – or “fragile” – enough the uncertainty regarding management strategies should be shared with patients, in that there could yet be an undefined disadvantage to conservative management. However, it is probably the case patients who did not undergo a drainage procedure and did not return for follow-up were asymptomatic and functioning well. The available data on long-term follow-up even better reinforces the case for conservative management, as need for additional surgical procedures and 12-month recurrences all favored the conservative arm.

These data do not address whether aspiration as an initial strategy has any value, whether in short-term functional improvement or similar long-term outcomes. Considering how well the conservative management cohort did, however, it may ultimately be challenging to show a specific advantage to adding an aspiration procedure. This may perhaps be addressed by future trials.

“Conservative versus Interventional Treatment for Spontaneous Pneumothorax”

https://www.nejm.org/doi/full/10.1056/NEJMoa1910775

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