Month: October 2019

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