Best Of AAST 2021: Comparing Two Different Doses Of Enoxaparin

Oh, look, my favorite topic! Prevention of venous thromboembolism (VTE) and complications. We’ve grown accustomed to using enoxaparin at the standard 30mg bid dose for a long time.  The orthopedic surgeons like to use 40mg qd, and there is some literature that shows this is reasonable for fracture patients.

The group at OHSU in Portland wanted to show that the single dose regimen is just as safe and effective as the bid dose. They performed a seven year, prospective, randomized trial of the two dose regimens. Weekly screening duplex exams were performed. The outcome measured was the occurrence of deep venous thrombosis (DVT) in the legs. They also examined missed doses, bleeding complications, and hospital length of stay.

Here are the factoids:

  • There were 267 total patients, 139 on the single dose regimen and 128 in the bid group
  • Average age was 49 and BMI was 28 in both groups
  • DVT occurred in 15 (11%) qd patients and 12 (9%) bid patients
  • Bleeding occurred in 19% of qd patients vs 14% of bid patients
  • There were fewer missed doses in the qd patients
  • None of the differences were statistically significant

The authors concluded that the qd dose was similar to the bid dose and is equally efficacious.

Bottom line: Hold on, now. First, this is a non-inferiority study. Daily dosing is presumed to be as good as twice daily dosing since there was no statistical difference seen between groups. This assumes that you have the statistical power (enough patients) to detect a difference. Is this the case here?

I pulled out my Sample Size calculator to check this over. I work things backwards to see the magnitude of difference that would have to be present for the given number of subjects. It looks like a sample size this small would only be able to detect a difference of 2x in the DVT occurrence result!

Lets look at this in simple terms. The absolute number of DVTs was actually higher in the qd group (11% vs 9%). So let’s say it is actually inferior to bid, meaning that the higher occurrence of DVT is real. Using the number of subjects here, the incidence could rise to 20% in the qd group and still not reach significance. 

The other major issue is the potential for selection bias. This study took place over 7 years. Yet only 267 were enrolled, or 38 patients per year. But this trauma center admits several thousand patients annually. If the enrollment criteria were so strict, the subjects probably don’t represent the general population. And if they weren’t, where did all the patients go? This is most likely a skewed study group.

I have lots of questions for the presenter and authors on this one!

  • Please show us your power calculations. Are you sure you have the statistical oomph to show non-inferiority?
  • Why did it take so long to accumulate 267 subjects? Show us the statistics for your overall trauma population to make sure they look the same.
  • Were you able to detect any other complications like pulmonary embolism?

Lots of questions here! Hopefully there’s much more information in the presentation!

Reference: A PROSPECTIVE RANDOMIZED TRIAL COMPARING TWO
STANDARD DOSES OF ENOXAPARIN FOR PREVENTION OF
THROMBOEMBOLISM IN TRAUMA. AAST 2021, Oral abstract 40.

Best Of AAST 2021: Individual Surgeon Outcomes In Trauma Laparotomy

Trauma programs use a number of quality indicators and PI filters to evaluate both individual and system performance. The emergent trauma laparotomy (ETL) is the index case for any trauma surgeon and is performed on a regular basis. However, this is one procedure where individual surgeon outcome is rarely benchmarked.

The trauma group in Birmingham AL performed a retrospective review of 242 ETLs performed at their hospital over a 14 month period. They then excluded patients who underwent resuscitative thoracotomy prior to the laparotomy. Rates of use of damage control and mortality at various time points were studied.

Here are the factoids:

The chart shows the survival rates after ETL at 24 hours (blue) and to discharge (gray) for 14 individual surgeons.

  • Six patients died intraoperatively and damage control laparotomy was performed in one third.
  • Mortality was 4% at 24 hours and 7% overall
  • ISS and time in ED were similar, but operative time varied substantially (40-469 minutes)
  • There were significant differences in individual surgeon mortality and use of damage control

The authors concluded that there were significant differences in outcomes by surgeon, and that more granular quality metrics should be developed for quality improvement.

Bottom line: I worry that this work is a superficial treatment of surgeon performance. The use of gross outcomes like death and use of damage control is not very helpful, in my opinion. There are so, so many other variables involved in who is likely to survive or the decision-making to consider the use of damage control. I am concerned that a simplistic retrospective review without most of those variables will lead to false conclusions.

It may be that there is a lot more information here that just couldn’t fit on the abstract page. In that case, the presentation should clear it all up.  But I am doubtful.

We have already reached a point in medicine where hospitals with better outcomes for patients with certain conditions can be identified. These centers should be selected preferentially to treat stroke or pancreatic cancer, or whatever there benchmark-proven expertise is. It really is time for this to begin to trickle down to individual providers. A specific surgeon should be encouraged to do what they are demonstrated to be really good at, and other surgeons should handle the things the first surgeon is only average at.

But I don’t think this study can provide the level of benchmarking to suggest changes to a surgeon’s practice or the selection of a specific surgeon for a procedure. A lot more work is needed to identify the pertinent variables needed to develop legitimate benchmarks.

Here are my questions for the presenter and authors:

  • Show us the details of all of the variables you analyzed (ISS, NISS, time in ED, etc) and the breakdown by surgeon.
  • Are there any other variables that influence the outcome that you wish you had collected?
  • There were an average of 17 cases per surgeon in your study. Is it possible to show statistical significance for anything given these small numbers?

The devil is in the details, and I hope these come out during the presentation!

Reference: IT’S TIME TO LOOK IN THE MIRROR: INDIVIDUAL SURGEON OUTCOMES AFTER EMERGENT TRUMA LAPAROTOMY. AAST 2021, oral abstract #38.

Best Of AAST 2021: Validating The “Brain Injury Guidelines” (BIG)

The Brain Injury  Guidelines (BIG) were developed to allow trauma programs to stratify head injuries in such a way as to better utilize resources such as hospital beds, CT scanning, and neurosurgical consultation. Injuries are stratified into three BIG categories, and management is based on it. Here is the stratification algorithm:

And here is the management algorithm based on the stratification above:

The AAST BIG Multi-Institutional Group set about validating this system to ensure that it was accurate and safe. They identified adult patients from nine high level trauma centers that had a positive initial head CT scan. They looked at the the need for neurosurgical intervention, change in neuro exam, progression on repeat head CT, any visits to the ED after discharge, and readmission for the injury within 30 days.

Here are the factoids:

  • About 2,000 patients were included in the study, with BIG1 = 15%, BIG2 = 15%, and BIG3 = 70% of patients
  • BIG1: no patients worsened, 1% had progression on CT, none required neurosurgical intervention, no readmits or ED visits
  • BIG2: 1% worsened clinically, 7% had progression on CT, none required neurosurgical intervention, no readmits or ED visits
  • All patients who required neurosurgical intervention were BIG3 (20% of patients)

The authors concluded that using the BIG criteria, CT scan use and neurosurgical consultation would have been decreased by 29%.

Bottom line: This is an exciting abstract! BIG has been around for awhile, and some centers have already started using it for planning the management of their TBI patients. This study provides some validation that the system works and keeps patients safe while being respectful of resource utilization. 

My only criticism is that the number of patients in the BIG1 and BIG2 categories is low (about 600 combined). Thus, our experience in these groups remains somewhat limited. However, the study is very promising, and more centers should consider adopting BIG to help them refine their management of TBI patients.

Reference: VALIDATING THE BRAIN INJURY GUIDELINES (BIG): RESULTS OF AN AAST PROSPECTIVE MULTI-INSTITUTIONAL TRIAL. AAST 2021, Oral abstract #25.

Best Of AAST: Delayed Treatment Of Blunt Carotid And Vertebral Injury

I recently published a series on blunt carotid and vertebral artery injury (BCVI). Today, I’ll review an AAST abstract that details the results of a multicenter study on the timing of medical treatment of this condition. This typically takes the form of anti-platelet agents, usually aspirin.

The trial collected prospective, observational data from 16 trauma centers. Patients had to receive medical therapy at some time after their injury or they were excluded. The stroke consequences of early vs late medical therapy were evaluated, where late was defined at > 24 hours.

Here are the factoids:

  • There were 636 BCVI included in the study
  • Median time to first medical therapy was 11 hours in the early group and 62 hours in the late group
  • ISS was higher in the delayed group (26 vs 22); although this was “statistically significant”, it is probably not a clinically significant difference
  • There was no increase in stroke rate with later administration of medical treatment

Bottom line: This is a very interesting study. We always worry about missing BCVI (see my previous post here), and now we know a little more about what happens if we do. The authors suggest that the stroke rate does not go up if medical management is delayed, say for some other potential bleeding issue.

This is a reasonably large data set, but the key thing to consider is the time frame observed. The median delay to medical management was only about 2.5 days. Were there any strokes involved in the patients with much longer delays? That is the real question. And were there any strokes that occurred despite early/immediate medical management?

The descriptive statistics and simple analyses presented do not provide all of the information we need. A stoke is a very significant adverse event for the patient. Statistical means are fine, but information on the specific patients who suffered one is necessary to truly understand this issue.

Here is my question for the presenter and authors:

  • Please break down the details on all patients who suffered a stroke. It will be very interesting to see if there were any in the early group and if there was a trend toward stroke in the very late tail data.

Reference: DOES TREATMENT DELAY FOR BLUNT CEREBROVASCULAR INJURY AFFECT STROKE RATE?: AN EAST MULTICENTERTRIAL. AAST 2021, Oral abstract #23.

Best Of AAST 2021: Liposomal Bupivacaine For Rib Fractures

The mainstays of rib fracture management are pain control and pulmonary toilet. The pain part of the equation can be managed in many ways, using topical, oral, IV, and injectable medications.

Rib blocks have been a mainstay for achieving some degree of local pain control. Classically, xylocaine was injected in the area around the costal nerve at or proximal to the fracture site. Then we found that if we combined the anesthetic agent with epinephrine, we could prolong the effect. New, longer-acting agents came around, and we could achieve a longer duration of action.

Then there is the new kid on the block: liposomal bupivacaine, also known as Exparel in the US.  The manufacturer was able to take molecules of bupivacaine and encapsulate them in a lipid membrane. When injected, these little liposomes slowly release their cargo, with a more prolonged anesthetic effect. Allegedly.

Sounds great! But does it work? The group at University of Cincinnati designed a prospective, double-blinded, randomized placebo control study of liposomal bupivacaine vs saline injection for pain control in up to six rib fractures. Subjects had significant injury as measured by their inability to achieve at least 50% of the desired inspiratory capacity. The authors monitored a number of respiratory parameters, as well as the pain score.

Here are the factoids:

  • Two cohorts of 50 patients were recruited, one received liposomal bupivacaine in up to six rib fractures, and the other received saline injections
  • The bupivacaine group achieved higher incentive spirometry volumes over the first two days, by about 200 cc
  • There was no change in daily pain scores in either group
  • Both groups showed a similar decrease in opioid use over time
  • Hospital and ICU lengths of stay were the same, and there were no complications or adverse events

Bottom line: Hmm. What’s going on here? There is a moderate amount of literature out there that does indicate a positive effect from liposomal bupivacaine in other conditions. But there are also some blinded, randomized studies that fail as well. So there are three possibilities:

  1. Liposomal bupivacaine isn’t a panacea, and works better in some situations than others
  2. This study failed to show a real difference for some reason
  3. A combination of both

This is a relatively small study, and the authors were not able to share their power analysis. They did not state if the spirometry volumes were significantly different, although I’m not sure 200 cc is clinically relevant. Maybe. But pain scores remained similar and opioid use declined as expected in both. 

These kinds of studies can be important. The difference in cost between injecting liposomal bupivacaine ($19 / ml) vs regular bupivacaine (10 cents / ml) vs saline/nothing (free) is striking. The premium price for the liposomal form needs to have a clear benefit or a cheaper product should be used.

Here are my questions for the presenter and authors:

  • Was your study big enough to show a result? Show us your power analysis.
  • How significant was the incentive spirometry result. Was the difference clinically noticeable?
  • What is your takeaway for this study? Your conclusion parrots the results. What will you do differently now, if anything?

Reference: INTERCOSTAL LIPOSOMAL BUPIVACAINE INJECTION FOR
RIB FRACTURES. AAST 2021, Oral abstract #20.

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