2019 Early Management of Acute Ischemic Stroke

Well, it’s 2019 – for another couple months – so there’s still time to update your Early Management of Acute Ischemic Stroke.

For what would otherwise sound to be a potentially underwhelming interval update, there is, in fact, a ton to unpack in here. Institutional stroke committees and regional EMS systems thrive on constant change, after all. Most of the changes are “clarity”, but there are many new recommendations, some of which are bland – promoting the use of EMS for stroke symptoms, for example – whereas others are even potentially controversial.

Some of the meat:

  • Expert opinion-based recommmendations to bypass local hospitals in preference of thrombectomy-capable facilities for patients ineligible for IV thrombolysis, but with symptoms of large vessel occlusions.
  • Several new recommendations promoting telestroke as a reasonable means of patient evaluation, even if it’s just telephone consultation.
  • A handful of new recommendations incorporating the use of MRI for stroke assessment, based on WAKE-UP, including the use of IV thrombolysis beyond 4.5 hours.
  • Two new recommendations regarding multimodal imaging in acute ischemic stroke. The first, non-controversial recommendation includes the use of CT perfusion or MRI-DWI for assessment of patients between 6 and 24 hours from symptom onset. However, when symptom onset is less than 6 hours, the new recommendation is to perform endovascular intervention based just on vessel status and ASPECTS. Throw out the high-value care guided by REVASCAT, SWIFT PRIME, EXTEND-IA, and ESCAPE and just treat based on the smaller effect sizes seen in THRACE and MR-CLEAN!
  • Surprisingly, explicit recommendation to withhold thrombolysis of mild non-disabling stroke based on PRISMS.
  • Thrombolysis with tenecteplase makes its first appearance as a reasonable alternative to alteplase.
  • A new recommendation to cover initiation of short-term dual antiplatelet therapy for minor stroke not treated with alteplase.
  • An entire massive new section with recommendations regarding in-hospital imaging modalities to help regarding secondary prevention of ischemic stroke.

There’s something in here for just about everyone!

“Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke.”
https://www.ncbi.nlm.nih.gov/pubmed/31662117

CRASH-3!

Tranexamic acid, an anti-fibrinolytic, helps reduce bleeding. When bleeding can be attenuated, patient-oriented outcomes related to bleeding can be improved. Its effect on outcomes, however, mirrors its clinical effect: quite small. In CRASH-2, general adult trauma with significant extracranial bleeding, the 28-day all-cause mortality reduction was 1.5%. In WOMAN, death due to bleeding from post-partum hemorrhage was reduced 0.4%.

Now, we address the use of TXA for intracranial bleeding. This has been evaluated before, however, in the TICH-2 trial. The primary outcome for TICH-2 was functional status at day 90, which was not reliably different between groups, nor was mortality at 90 days. There were, however, only 2,325 participants in this trial. CRASH-3, on the other hand, has enrolled 12,737.

With nearly six times as many patients, there are likewise about six times as many events – leading to detection of a small difference in head injury-related death, 18.5% in those receiving TXA versus 19.8% receiving placebo. Broken down further, the authors refine source of this difference primarily to those receiving TXA within three hours, and in those with mild and moderate head injury. Beyond three hours and in those with severe head injury, TXA administration was not associated with any reliable benefit (or harm).

However, any enthusiasm for TXA must evaporate when the results are no longer parsed based solely on head injury-related death. All-cause mortality is ultimately no different, with a reported RR of 0·96 (0·89–1·04). It would certainly be preferable if TXA were clearly beneficial, as opposed to observing an excess of non-head injury-related deaths to counterbalance its seeming benefit. Furthermore, looking at their various measures of disability, no clear advantage is seen favoring TXA. The ultimate flavor of their observations are somewhat embittered by these loamy morsels.

What should we do with these results? Well, probably, what we’ll likely do is expand the use of TXA. The good news is this is unlikely to be harmful and TXA is inexpensive. The bad news is, the minimal effect TXA does have on attenuating bleeding simply doesn’t result in a easily measured excess of functional adults post-injury. Practice variation is certainly acceptable surrounding the use of TXA, but we certainly ought not be dogmatic about the necessity of its application in isolated head injury.

“Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext

The Vitamins in Sepsis Parade Begins

A couple years back, we saw one of the first reports describing the potential efficacy of treating sepsis with a cocktail of vitamin C, thiamine, and steroids. These observational findings have been viewed with a healthy dose of skepticism while awaiting prospective, randomized evidence with regard to their validity.

Well, here’s one of the first: a short communication from CITRIS-ALI, a randomized clinical trial that almost, sort of, not quite, addresses the question of interest. This study was designed and initiated well before the aforementioned observational report, and it examines vitamin C monotherapy in patients with sepsis and acute respiratory distress syndrome. Their primary outcome and goal was to see if vitamin C could reduce sequential organ failure assessment scores, along with biological markers of inflammation and vascular injury.

With 1,262 patients screened leading to 167 patients receiving their randomized interventions, the answer is: no. Neither modified SOFA scores, c-reactive protein, nor thrombomodulin were different between groups.

But, wait! There’s more! In fact, 46 additional pre-specified secondary outcomes – 43 of which showed no difference. These included both the esoteric – angiopoietin-2 levels, tissue factor pathway inhibitor – and patient-oriented. It is these patient-oriented outcomes that pique the most interest: at 28 days, mortality in the vitamin C group was 29.8%, as compared with 46.3% with placebo. Ventilator-free days and ICU-free days similarly favored the vitamin C cohort.

So, interesting data incapable of informing practice. Another small sample, designed (appropriately) around a different target and primary outcome, with a secondary outcome still falling into the realm of hypothesis-generating. This will likely influence no one. Anyone already giving vitamins in sepsis – cheap, likely harmless – will continue to do so, and those awaiting a more informative trial will, also, continue to do so.

“Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure”

https://jamanetwork.com/journals/jama/fullarticle/2752063

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

  • Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
  • Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
  • Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
  • The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
  • Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
  • No routine empiric anerobic coverage for suspected aspiration pneumonia.
  • No routine steroids for CAP, even severe.
  • Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
  • No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

It’s Lefamulin Time

New antimicrobials – particularly those with novel mechanism of action – are rare. Lefamulin, a pleuromutilin class antibiotic, is not new, but it’s new to humans – or, even more specifically, new to oral and intravenous availability in humans.

This article in JAMA details LEAP-2, the sequel (of course) to LEAP-1. This clinical trial demonstrates the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of generally mild community-acquired pneumonia. LEAP-1, as I’m certain you recall, demonstrated its non-inferiority as an intravenous-to-oral regimen for slightly-less-mild CAP in whom hospitalization was reasonable. Without belaboring the results too greatly, “early clinical response in the intention to treat population” and “test of cure in modified intention to treat populations” were generally similar, with response rates of about 90% for each arm. However, lefamulin is certainly less well-tolerated – diarrhea, nausea, and vomiting far exceeded the frequency observed in the moxifloxacin cohort.

These are likely valid results with respect to efficacy and a 10% non-inferiority margin, considering pleuromutilin antibiotics have been used effectively in animals for decades. This was, however, a tightly-controlled trial, narrowly targeted at meeting the threshold for approval in Europe and the United States (i.e., 50% of patients required to be PORT Class II, so 50.4% of them were). All authors, study procedures, and analyses were overseen by the sponsor, and trial sites were scattered across the (somewhat) developing world. Irregularities regarding efficacy differences and assessments were seen at several sites and addressed in the supplementary appendix, noting mostly the exclusion of results from these sites would not have affected the overall trial outcome. All these signals, however, do raise concerns regarding underreporting of adverse events and systematic minimization of any efficacy differences.

It’s splendid to have a new option for cases of multidrug resistance. For $200 to $300 a day, however, no need to indulge unnecessarily – or be the first on your block to drive the new hotness.

“Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia”
https://jamanetwork.com/journals/jama/fullarticle/2752331

Saving Lives with Lifesaving Devices

Automated electronic defibrillators are quite useful in many cases of out-of-hospital cardiac arrest – specifically, those so-called “shockable rhythms” in which defibrillation is indicated. Ventricular fibrillation, if treated with only bystander conventional cardiopulmonary resuscitation, has dismal survival. However, when no AED is available, the issue is mooted.

This is an interesting simulation exercise looking to improve access to AEDs such that availability might be improved in cases of cardiac arrest. These authors pulled every AED location in Denmark, along with the locations of all OHCAs between 2007 and 2016. Then, they used all OHCA from 1994 until 2007 as their “training set” to help derive an optimal location for AED placement with which to simulate. Optimal AED placements were dichotomized into “intervention #1” and “intervention #2” based on whether their building location provided business-hours access, or 24/7 access.

In the “real world” of 2007 to 2016, AED coverage of OHCA was 22.0%, leading to 14.6% bystander defibrillation. Based on their simulations and optimization, these authors propose potential 33.4% and 43.1% coverage, depending on business hours, leading to increases in bystander defibrillation of 22.5% and 26.9%. This improved coverage and bystander defibrillation would give an absolute increase in survival, based on the observed rate, of 3.4% and 4.1% over the study period.

This is obviously a simulation, meaning all these projected numbers are ficticious and subject to the imprecision of the inputs, along with extrapolated outcomes. However, the underlying principle of trying to intelligently match AED access to OHCA volume is certainly reasonable. It is hard to argue against distributing a limited resource in some data-driven fashion.

“In Silico Trial of Optimized Versus Actual Public Defibrillator Locations”
https://www.sciencedirect.com/science/article/pii/S0735109719361649

Counterpoint: Topical Anesthetics for Corneal Abrasions

We’ve seen a few articles recently discussing the potential utility of topical anesthetics for analgesia for corneal abrasions. The general point: there’s no consistent, modern evidence of harm, so why should we cling to older ways?

Counterpoint from the corneal specialist community: cling to old ways.

In this long correspondence, the authors detail the physiologic basis for their opposition to topical anesthetics as it relates to stimulation of endothelial growth. They follow this up with a three question survey regarding the practice, distributed to “an international community of cornea trained specialists”.

The clear winner in each of their three questions: “strongly disagree” with provision of topical anesthetics for acute corneal abrasions.

Interestingly, they also conflate these results with lack of justification for a clinical trial to further explore the safety and efficacy of such use:

“Often when there is a difference in clinical practice or clinical equipoise, there is an opportunity for a clinical trial. However, it is our hypothesis that within the ophthalmology community, there is not equipoise with respect to our practice of not prescribing topical anesthetics after traumatic corneal abrasions.”

I think it’s clear these specialists are making valid points regarding the potential for topical anesthetic abuse, but their citations hardly support their practice stance. I do agree, at least, regarding the lack of utility of clinical trials – but not because their use is so dangerous it cannot be tested. Rather, any clinical trial simply would be of low value as adverse events would be so rare it would be unlikely to reliably detect a difference between management strategies. It is clear topical anesthetic use will not be safe in all clinical situations, but it is rather more appropriate to provide guidance on the proper use of topic anesthetics than to simply ban them completely while continuing to cite the same anachronistic, limited evidence.

“Cornea Specialists Do Not Recommend Routine Usage of Topical Anesthetics for Corneal Abrasions”
https://www.ncbi.nlm.nih.gov/pubmed/31445551

The Antibiotic Penalty on Blood Cultures

As the administrative team likes to remind us: blood cultures before antibiotics.

Blood cultures before antibiotics.

Blood cultures? Before antibiotics.

What’s the point, we say – aren’t the antibiotics the actual life-saving intervention? And the answer, when relevant, ties into identifying the specific susceptibility of the infective agent, such that antibiotics may ultimately be narrowed to the minimum necessary for cure. It’s a noble premise, at least.

But, so, what does happen when you give antibiotics first?

At least one recent retrospective study has pulled data from their health system showing a clear decrease in blood culture positivity following administration of antibiotics, but these results may be limited by potential differences between groups. In contrast, this clever little study looks at it prospectively: the same 325 Emergency Department patients with “severe manifestation of” sepsis – hypotensive or lactate >4 mmol/L – received blood culture draws both prior to, and just following, antibiotic administration.

Before antibiotics: 31.4% positive blood cultures.

After antibiotics: 19.4% positive blood cultures.

It is not a perfect study by any means, but a long story short: if you’re going to go to the trouble of drawing and processing blood cultures, draw them before you start antimicrobial treatment. But, clearly, the antimicrobials are doing their job – do it expeditiously such that your patient does not suffer from unwanted delay.

“Blood Culture Results Before and After Antimicrobial Administration in
Patients With Severe Manifestations of Sepsis”
https://annals.org/aim/fullarticle/2751453/blood-culture-results-before-after-antimicrobial-administration-patients-severe-manifestations

Let’s Not Treat the Asymptomatic (Urine)

It’s a fairly common picture: the altered/declining/demented/elderly, with a small leukocytosis, and some positive elements on a urinalysis – but no clear symptoms of urinary tract infection. For lack of a better explanation, perhaps, treatment is begun with antibiotics. The benefit is uncertain, but, at the least it is more likely to benefit than harm?

This retrospective study, within the scope of its limitations, finds no reliable benefit to treatment, and more likely harms. This study performed chart reviews on 2,733 hospitalized patients with “asymptomatic bacteriuria”, as defined as a positive urine culture in the absence of documented Infectious Diseases Society of America criteria for UTI. Constitutional or non-specific symptoms in those unable to specifically report (e.g, dementia, AMS) were not considered as consistent with UTI unless multiple systemic signs of infection were also present.

Not only did nearly 80% of patients identified as ASB receive antibiotics, these authors were unable to shed light on any value of treatment. Treatment of ASB was more common in the scenario above, but was also widespread in patients capable of reporting symptoms yet having none documented. The dependence on retrospective chart abstraction limits the accuracy of their observations, but they have face validity.

Patient-oriented outcomes associated with either antibiotic treatment or non-treatment were 30-day mortality, 30-day readmission, 30-day post-discharge Emergency Department visit, C. diff infection, and duration of hospitalization. Most adjusted and unadjusted odds ratios for poorer outcomes were associated with treating ASB, but these differences were generally not statistically significant. Duration of hospitalization, however, was statistically associated with antibiotic treatment. This may be a spurious finding relating to contextual clinical confounders, but it may also represent an element of diagnostic inertia distracting from the true underlying etiology relating to hospitalization.

Regardless, consistent with this journal’s series feature “Less is More”, yet another instance in which common practice does not easily lend itself to confirmation of value.

“Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2748454

Women are Just as Typical as Men?

It’s somewhat dogmatic in medicine to teach men and women present with differing symptoms during myocardial infarction. Women are, as they say, more likely to have “atypical” symptoms.

This study differs slightly from previous accounting of the presenting symptoms of men and women with potential cardiac ischemia. This is a pre-planned, prospective analysis accompanying the High-STEACS trial, featuring in part an evaluation of gender-specific cut-offs for high-sensitivity troponin. As part of this trial, rather than using a typical “conventional” troponin cut-off for the 99th percentile of 50 ng/L, they used 16 ng/L for women and 34 ng/L for men. These cut-offs were correlated with clinical information to determine the diagnosis of type I myocardial infarction, generating a prevalence of 16% for men and 12% for women among the 1,941 included in the analysis.

Among these, authors found similar prevalence of “typical” symptoms – dull, tight, pressure, aching, crushing, in the chest, arm or jaw – in women as men considered for potential acute coronary syndrome. Among those ultimately diagnosed with type I MI, women were actually slightly more likely to manifest “typical” symptoms – 77% versus 59%. The authors did not find the presence of multiple “typical” symptoms to have a terribly useful positive likelihood ratio for MI in either women or men.

Unfortunately, these data run into unavoidable selection bias: “All patients over 18 years of age in whom the attending clinician requested cardiac troponin for suspected acute coronary syndrome were eligible for inclusion.” Therefore, the so-called “atypical” presentation in which ACS was not suspected – i.e., the women with “atypical” presentations – would be, by definition, missed. It may be the difference between men and women is not as great as originally thought – but these data cannot definitively answer the question.

“Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex-Specific Criteria”
https://www.ahajournals.org/doi/10.1161/JAHA.119.012307