Ryan Radecki

🤷‍♂️ Vitamins in Sepsis Again

The VITAMINS trial was not the only trial investigating the efficacy of the hydrocortisone/vitamin C/thiamine cocktail in severe sepsis – and will thus not be the last word on the matter, by any chance. This is one of what is sure to be a slow trickle of other relevant data – as much as anything can break through the cacophony of the coronavirus pandemic.

This is a small trial, just 137 patients, and they used ascorbic acid 1,500 mg q6h, thiamine 200 mg q12, and hydrocortisone 50 mg q6h or a matching saline placebo for a four day course of treatment. Open-label corticosteroids were permissible per the clinical judgement of treating clinicians. The primary outcome was – wait for it – resolution of shock and change in SOFA score. This is, unfortunately, a change from their original primary outcome – in-hospital mortality. The original primary outcome is not mentioned in their manuscript, however, and includes a power calculation based on their secondary outcome – and this power calculation serendipitously matches their original anticipated study size as seen on clinicaltrials.gov.

There are circumstances in which changing the primary outcome is reasonable based on new, outside information obtained during the course of a study. That is not the case here. Moreover, and less appetizing, the new primary outcome is conveniently the only outcome measured significantly favoring the intervention. The authors tracked WBC counts, platelet counts, lactates, SOFA scores, fluid balance, procalcitonin clearance, ICU length-of-stay, hospital mortality, ICU mortality, and more, ad nauseaum. It is clear their original primary outcome would not have reached statistical significance because mortality was far too low – 16% with the intervention, 19% for control – based on sample size. However, the correct thing to do is simply run the trial out and have a reasonable academic discussion of the observed findings, not change to a disease-oriented surrogate.

Because, after all this, the authors make a fair bit of hay of their observed difference in shock resolution, a finding favoring the intervention by nearly a day. However, there were differences[1] in the groups at baseline specifically regarding the initiation of vasopressors – and this probably trickles down to the duration of vasopressors, as well. This study probably mostly shows just how difficult it is to do a study in intensive care, and how robust a sample size is required. Giving patients vitamins is unlikely to cause specific harms, but it doesn’t seem to be all that helpful. Remember – reliably useful treatments give reliably positive results.

“Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial”
https://www.sciencedirect.com/science/article/pii/S0012369220304554

Differences reported with a p-value, no less. There is no reason to report p-values for baseline characteristics in a randomized trial. A p-value here describes the likelihood an observation occurred by chance alone, but, obviously, because it was randomized, the chance it occurred by chance alone is 100%.

Selective vs. Universal Screening for BCVI

Chasing down cerebrovascular injury is a controversial topic. The incidence of injury to carotid or vertebral arteries following blunt trauma is extremely low, with relative rarity varying by practice setting. Because of its general infrequency, many settings utilize the “Memphis” or “Denver” screening criteria to improve the value of imaging.

These authors, however, describe their implementation of a universal screening protocol for BCVI as routine component of their “whole-body” CT for “all major adult blunt trauma activations”. The data set analyzed is a retrospective local trauma registry from their level 1 trauma center, and 4,687 activations fulfilled their inclusion criteria. The overall incidence of BCVI in their population was 2.7%, with about half of those being grade 3 or higher (pseudoaneurysm or worse).

Based on case review of these 126 patients with BCVIs, only 91 (72%) would have met the current American College of Surgeons guidelines for imaging, with a handful additional more picked up by expanded Denver criteria. The authors’ conclusion – universal screening should be considered – ties in a bit with their bias towards whole-body CT, presuming these additional detected injuries represent potential reduced downstream morbidity and mortality.

It should be clear, however, these data have somewhat limited generalizability to most of Emergency Medicine. The individuals with BCVI in their cohort suffered substantial numbers of skull base fractures, cervical spine fractures, traumatic brain injuries, and had in-hospital mortality of 12.7%. Outside the context of major trauma, universal screening for BCVI will be of limited value. For the vast majority of us, continuing to refer to the most recent EAST recommendations for selective screening remains a reasonable practice. In the narrower context of major trauma referrals, these data could inform more expansive screening protocols, while universal screening for all major trauma is still likely one step too far.

“Blunt Cerebrovascular Injury – The Case for Universal Screening”
https://journals.lww.com/jtrauma/Abstract/9000/BLUNT_CEREBROVASCULAR_INJURY___THE_CASE_FOR.97839.aspx

New Troponin, Same as Old Troponin?

It doesn’t take more than a quick search through the archives to notice a great deal of gnashing of teeth over the introduction of high-sensitivity troponin. The perpetual concern: trade-offs with sensitivity and specificity, leading to downstream increased resource utilization.

This brief research letter is basically good news: the Mayo Clinic hospital system rolled out high-sensitivity troponin assays and very little changed. Looking at about 54,000 patients divided equally into pre- and post- periods, the diagnosis of myocardial infarction increased significantly. However, most of the change was coded as Type 2 MI, rather than an acute coronary syndrome, leading to little change in resource use – no difference in admissions, echocardiography, stress testing, or angiography.

There’s brief allusion in the article to the underlying protocols in place – in which patients are typically assessed using HEART, along with a system of champions and education supporting the change. Assuming these retrospective coded data accurately reflect practice, it is likely these concerted efforts prevented misinterpretation of detectable troponin levels – hence the increase in Type 2 MI. Implementation of these assays in other health systems may not reflect these same successes, but it is reasonable to expect the on-ramp for high-sensitivity troponin has likely now been long enough most are now familiar with their interpretation.

Finally, the ultimate better question might be – if high-sensitivity assays didn’t clearly impact care, what value do they confer? If there are no measurable improvements in diagnosis of acute MI, is there much utility? However, these data do not provide insight into whether there are downstream changes in medication management potentially reducing long-term cardiovascular adverse outcomes – nor, likewise, any medication changes resulting in increased costs and adverse outcomes without an improvement in cardiovascular health. And, asking these questions is likely moot, regardless – these assays are here and here to stay.

“Implementing High-Sensitivity Cardiac Troponin T in a US Regional Healthcare System”
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.045480

Settling the Thrombolysis Before Thrombectomy Question

… taking a quick break from combating misinformation in our age of public health emergency to note this important non-COVID-19 article from the New England Journal of Medicine. Today’s question: is alteplase necessary prior to endovascular thrombectomy in acute ischemic stroke?

“It depends”.

This isn’t the first study to hit the light of day, but the largest. Previously, the “Randomized Study of Endovascular Therapy with Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke with ICA and M1 Occlusion (SKIP)” was presented at the International Stroke Conference earlier this year. Their study enrolled 204 patients and found no clinically important differences, particularly with respect to their primary outcome of mRS 0-2. Symptomatic intracranial hemorrhage was increased by a couple percent in those with bridging therapy, and there was a small excess of deaths – but, of course, none of these were “statistically significant”.

This study is three times the size, with 656 enrolled. Specifically, these are patients with large-vessel, anterior circulation occlusions for whom treatment can be initiated within 4.5 hours – the role for which alteplase is currently enshrined in the guidelines. And, these results are remarkably consistent with the prior observations. The mRS scores were, again, virtually identical. There was, again, an 2% absolute increase in sICH favoring the direct to endovascular therapy group, likely contributing to an observed ~1% excess deaths in the alteplase cohort.

The only element in “favor” of alteplase bridging is the surrogate outcome of successful reperfusion. There was a 4.6% excess of successful reperfusion before thrombectomy in the alteplase cohort, an advantage maintained to final angiographic recanalization at 24-72 hours. However, this small difference simply has minimal reliable effect on clinical outcomes – reperfusion is not synonymous with tissue salvage.

The net result of these observations ought to be the exclusion of thrombolytic therapy prior to endovascular intervention for those patients with immediate catheterization lab availability. Many patients, however, have prolonged transport times prior to endovascular intervention, and this study does not address this situation. However, prior studies likely demonstrate tenecteplase is more effective at obtaining early reperfusion in patients with large vessel occlusion, and probably should be the thrombolytic of choice in a “drip and ship” situation – if not all situations.

At this point, at least, the onus ought to rather be on proving clinical advantage to alteplase/tenecteplase prior to endovascular intevention. Given the consistent costs and harms of thrombolytic therapy, it is time to prove its value, rather than the converse.

“Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa2001123

Covid-19 is EVERYWHERE

That lede encapsulates the underlying subtext of the most recent New England Journal of Medicine publication regarding the spread of coronavirus. This article is very simple, and – importantly – very limited.

These authors from Columbia University in New York, New York, simply supply a short research letter describing their experience screening pregnant patients for SARS-CoV-2 infection at their obstetrical intake prior to delivery. Between March 22nd and April 4th, there were 215 women who delivered at New York-Presbyterian and Columbia University Irving. Four were febrile and symptomatic at admission and all tested positive. However, an additional 29 patients who were not experiencing symptoms of Covid-19 also tested positive by nasophargyneal swab and RT-PCR. Thus, the big freak out: 15% of this convenience sample were asymptomatic at time of diagnosis.

Many important limitations may preclude its generalizability to clinical practice and public health policy:

New York was in the midst of a substantial outbreak during sampling, with certainly higher background prevalence than most communities.
Full follow-up was not completed to determine whether the “asymptomatic” patients were truly “asymptomatic” or actually “presymptomatic”. Truly asymptomatic infection would imply vastly larger pools of infected and/or recovered citizens. This would drive down case-fatality rates and contribute to “herd immunity”. Presymptomatic infection is distinctly different, however, as these patients would be reflected in our current methods of (under)counting cases.
Pregnant women are not representative of the general populace, neither in their overall immune system physiology, nor with respect to the frequency with which they leave the home and access healthcare systems during a high-risk period.
It’s simply a convenience sample of 215 patients, diminishing the precision of their measurements.

The big takeaway here mostly has implications for testing. In areas with high prevalence of circulating infection – particularly circulating, undetected infection – routine screening at hospital admission should probably be performed. Right now, that is basically everywhere – so, in the interests in protecting healthcare workers and staff, all patients being admitted to the hospital ought to be screened, if possible. The other implication is reinforcement of our larger testing needs, and the already-known risks of presymptomatic viral shedding. Contact tracing and testing will be critical to stamping out local flare ups of disease – and we will need millions more tests than we currently perform.

“Universal Screening for SARS-CoV-2 in Women Admitted for Delivery”
https://www.nejm.org/doi/full/10.1056/NEJMc2009316

Update on Hydroxychloroquine and Azithromycin

It’s the French team from Marseille again – with more data on hydroxychloroquine and azithromycin.

You may remember them from the first, tiny uncontrolled trial featuring hydroxychloroquine monotherapy, and then combination therapy with hydroxychloroquine and azithromycin, with “untreated patients from another center” as their negative controls. This trial, with its grand total of 36 patients has been touted as a miraculous success – as opposed to a small 30 patient trial in China that was unrevealing.

Now we have 80 patients – but worse, still, it is even without any sort of controlled comparison, let alone a randomized, controlled comparison. Minimal enrollment criteria are noted in the publication, but they do note 6 patients are a carryover from their first study. It appears all patients receiving treatment for at least 3 days and received at least 6 days of follow-up were included in the analysis.

The standard treatment protocol is 200mg hydroxychloroquine three times a day, along with a typical 500mg/250mg azithromycin 5 day course. Those with pneumonia and NEWS scores ≥5 received ceftriaxone, as well.

There’s almost no point in mentioning a “primary outcome”, but effectively a good outcome is alive and discharged. Data were collected on viral culture Ct value (the number of amplification cycles required to obtain a positive result).

Overall, 65 of 80 (81.3%) improved and were discharged. One patient was admitted to the ICU and died on day 7 after initiation of treatment. Others have had waxing and waning clinical course in the hospital. Viral culture results, unsurprisingly, mirrored clinical improvement.

The authors infuriatingly suggest: “We believe other teams should urgently evaluate this cost-effective therapeutic strategy.” It is close to unethical to call for others to investigate these agents when they clearly have the means to do so themselves.

The lack of a control group renders these results uninterpretable. Further, the mention in results of “six days of follow-up” for analysis suggests survivorship bias. For a treatment already in widespread use (and misuse), we remain woefully underinformed regarding its true effectiveness and clinical utility.

“Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study”
https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

#COVID19

As you may have noticed, the global pandemic is consuming a bit of attention these days.

I’ve been putting most of my efforts into rapid-response threads to new literature and preprints on Twitter: @emlitofnote. You can follow along there as we try to rapidly titrate and disseminate effective strategies for dealing with this scourge.

I hope we will all return to normalcy in due time.

Potpourri

Just a quick-hit collection of articles I’ve wanted to highlight/catalogue for future reference, but couldn’t find the time for deep dives into each:

Shared Decision Making in Patients With Suspected Uncomplicated Ureterolithiasis: A Decision Aid Development Study.
For this common clinical scenario in the Emergency Department, the authors have developed a patient-facing packet to facilitate shared decision-making. However, more important than the product, is the process these authors have described for its creation. A similar roadmap could be followed to address similar opportunities in your department.

Reduction of Inappropriate Antibiotic Use and Improved Outcomes by Implementation of an Algorithm-Based Clinical Guideline for Nonpurulent Skin and Soft Tissue Infections.
Amazing – using the correct antibiotics reduces treatment failures and, likewise, treatment failures necessitating admission to the hospital. This is an effort-intensive intervention featuring provider education and individual prescribing feedback, but, given the limitations, can be considered a change management success. Whether this can be replicated at your institution will depend on many cultural factors.

Utility of INR For Prediction of Delayed Intracranial Hemorrhage Among Warfarin Users with Head Injury.
Here’s a topic with a ton of practice variation – do you admit patients with closed head injury on anticoagulation for observation? This retrospective review of those patients just on warfarin tries to make the case patients with INR <2 are safe for discharge, whereas those with higher scores are not. Again, however, the yield of observation is somewhere south of 1% in their entire therapeutic cohort, making it truly challenging to find the inflection point of value. Another opportunity for shared decision-making?

Performance of Novel High-Sensitivity Cardiac Troponin I Assays for 0/1-Hour and 0/2- to 3-Hour Evaluations for Acute Myocardial Infarction: Results From the HIGH-US Study.
A detailed look at high-sensitivity Troponin I rule-in/rule-out algorithms suggests a 0/1-hour strategy is similar to a 0/3-hour strategy. Overall, while the disposition of patients is likely to be more rapid from the 0/1 hour strategy, a greater proportion of patients ultimately fall into the “intermediate” zone requiring further observation and diagnostics. Certainly, combinations of hsTnI and other risk-stratification instruments ought to mean the majority of patients with straightforward chest pain presentations may be discharged from the Emergency Department.

Randomized Clinical Trial of IV Acetaminophen as an Adjunct to IV Hydromorphone for Acute Severe Pain in Emergency Department Patients.
In this trial, patients receiving hydromorphone were randomized to receive adjunctive treatment with IV acetaminophen or placebo. With 159 patients, they found advantages to the multi-modal approach favoring the addition of acetaminophen – but the confidence interval for their primary outcome crossed unity by 0.01. The authors conclude this is a negative trial, but it rather seems to me there’s certainly no harm in adding acetaminophen (it need not be IV) – adding it likely has a favorable effect, even if the effect size may not be large.

Effect of No Prehydration vs Sodium Bicarbonate Prehydration Prior to Contrast-Enhanced Computed Tomography in the Prevention of Postcontrast Acute Kidney Injury in Adults With Chronic Kidney Disease: The Kompas Randomized Clinical Trial.
In news surprising no one, another trial fails to show benefit of prehydration in staving off post-contrast exposure acute kidney injury. As seen on Twitter, rather than “contrast-induced nephropathy”, the clinical paradigm is effectively “contrast-adjacent nephropathy.” The impairment in renal function is associated with the underlying medical illness and not the exposure to IV contrast. Thus, no intervention – such as prehydration – can prevent such.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.
This interesting observational study evaluated patients with a diagnosis of non-ST elevation acute coronary syndrome using coronary CT angiography prior to invasive coronary angiography. The good news: CT angiography was probably useful at excluding obstructive coronary disease. The bad news: nearly 70% of patients had a coronary stenosis identified on invasive angiography, so patient selection prior to CT angiography will be important to improve the value of using it as a screen to prevent invasive angiography.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.
As we watch our healthcare delivery system struggle and groan under the various strains and burdens, one of the culprits has always been the influence of pharmaceutical/device manufacturers targeting investments to improve uptake of their products. In this observational analysis of the OpenPayments database, these authors identified the recipients of financial support from the manufacturers of endovascular devices. About 16% of vascular neurologists received funding from industry, but over 75% could be identified as “influencers” – chiefs of staff, department chairs, or similar. Pharma et al should always be remembered they are serving the interests of owners and shareholders, and not patients and our healthcare system.

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