Best Of EAST #15: Prehospital TXA

The world is divided into trauma centers that are TXA believers and those that are TXA nonbelievers. It all depends on how one interprets the CRASH-2 data and subsequent studies. Then came CRASH-3 with TXA use for patients with TBI. This large study found improved survival in patients with mild to moderate head injury when given “early.”

The group at Oregon Health Science University tried to better define this concept of “early.” They examined early vs later administration of TXA in patients with moderate to severe TBI. Note that this degree of head injury is a bit different than CRASH-3 (mild to moderate in CRASH-3 and moderate to severe in this one). This was a multicenter trial that included patients with GCS < 12 and who were hypotensive with SBP < 90. Patients received either a 1g bolus followed by a 1g infusion over 8 hours, or a 2 g bolus only. The authors subdivided these patients into early administration (<45 minutes after injury) or late (45 minutes to 2 hours after injury).

Here are the factoids:

  • There were 354 patients in the early administration group and 259 in the late group
  • All outcomes, including 1 month and 6 month mortality and the extended Glasgow outcome scale were not significantly different between early and late groups (exact numbers were not given)
  • There was no difference in secondary complications between the groups (again, exact numbers or complication types were not given)

The authors concluded that there was no difference in outcomes in early vs later administration of TXA in these head injured patients. They suggest that patients can be given TXA anytime within two hours without loss of benefit.

Bottom line: Essentially, this ends up as a noninferiority study. The biggest question with this type of study is, do you have enough subjects to detect a significant difference? Taken to an extreme, let’s say you have 5 patients who receive a drug who are compared to 5 who did not for some mystery condition. Three who did not get the drug die (60% mortality), but only two who get it do (40% mortality). In relative terms, there was 33% decrease in mortality with the drug. But in absolute terms, it was one patient. Would anyone see this as a significant result with such small numbers?

But now multiply by a thousand, and 300 die without the drug and only 200 die who were given it. The relative difference is the same, but the absolute difference is beginning to look large and significant.

So the smaller study won’t meet the test of significance but the larger one will. The key question in the TXA study here is, do they have enough patients enrolled to show there is no real difference between the groups? I love doing back of the napkin power analyses, and I admit I certainly don’t have all the numbers and probabilities needed for a precise calculation. But the groups sizes in this study (354 vs 259) seem a bit small to achieve significance unless there are large disparities in outcomes. 

I certainly recognize that it’s just not possible to put all the relevant information for a research project into a four paragraph abstract. One would need to be able to submit 12 slide PowerPoint decks. So I’m sure more info will be available as I take in the presentation next Friday.

Here are my questions for the authors and presenter:

  • The study is nicely designed as a randomized, double-blind trial, but how did you blind one vs two doses? Did everyone get an infusion of something, TXA vs saline?
  • Why did you select 45 minutes as the cutoff for early vs late administration? Was this arbitrary or is it based some data?
  • Show us the power analysis that demonstrates the total number of patients in the study is sufficient to show us true non-significance in your results.
  • And I’m sure you will show the actual survival and complications numbers (and type) in the presentation, since they were not available in the abstract.


Best Of EAST #14: Trauma Center Access

The trauma group at MetroHealth in Cleveland has previously published a paper that examined the impact of Level I trauma centers in close proximity on their surrounding population. They have expanded this work to look at changes in the number of trauma centers of any level over a five year period and the populations that they serve across the US. The group was interested in elucidating the number of centers that opened in previously unserved areas, and the whether these areas were economically disadvantaged.

They used a list of state designated trauma centers maintained by the American Trauma Society. Level I and II centers were grouped together, as were Levels III through V. Census tracts around centers were categorized as “served” if the population surrounding it was within a 30 minute drive time of the center.

Here are the factoids:

  • The number of trauma centers increased by 256 to a total of 2140 in 2019, and 82% of these were Levels III-V
  • Nationwide coverage in terms of census tracts served increased from 75% to 80%
  • The increase in total population served was similar, rising from 76% to 79%
  • 91% of new Level I-II centers were in areas that were already served by other high level centers, and 86% of new Level III-V centers were in already served areas
  • New Level III-V centers were opened in areas with higher poverty than Level I-II centers (16% vs 13%)

The authors concluded that the numbers of trauma centers is increasing over time, but that more Level III-V centers are moving into underserved areas.

Bottom line: The authors have identified a novel way to suggest the financial motivations of opening trauma centers. When trauma systems were first implemented, there was an overall goal to provide coverage for the general population. But only a few states wrote guidelines that would attempt to evenly and equitably distribute new centers within and across counties.

The American College of Surgeons wrote a white paper and created a tool to assist in determining how many trauma centers were needed to serve a given population. Unfortunately, implementation of the tool was left to the states, and their legislatures had little interest in adding it to their system regulations after the fact.

So in some states, it’s like the wild, wild west with new centers opening almost next door to established and storied trauma hospitals. This abstract demonstrates that this phenomenon is real. But unfortunately, Pandora’s box was opened long ago and I don’t see that anything will change to address this situation in the foreseeable future.

Here are my questions for the authors and presenter:

  • Are the trends you identified general ones across the US, or are they focused in particular states?
  • Do you have any information on the impact of this trend on already existing trauma centers?
  • Can you speculate about what can be done to ameliorate this trend going forward?

This is a fascinating abstract about a non-clinical issue that has major implications for existing trauma programs (and especially certain states) well into the future.


Best Of EAST #13: Whole Blood And Hypocalcemia

Hypocalcemia has long been known to exacerbate coagulopathy. Calcium is involved at several points in the coagulation cascade. Once serum levels drop below about 0.25 mmol/L (normal value 1.2-1.4 mmol/L) thrombin generation and clot formation cease. Although levels this low are probably rare, anything between this low and the normal level can significantly lower clot strength.

Trauma patients are more likely to have bleeding issues than most, and trauma professionals do their best to avoid coagulopathy. Unfortunately, the products we use to replace shed blood are preserved with citrate, which binds calcium. Given in even modest to large quantities, transfusion itself can lead to hypocalcemia.

Most blood transfused in the US has been broken down into separate components (packed cells (PRBC), plasma, platelets) and the effect on calcium levels is well known. The trauma group at Oregon Health Sciences University studied the impact on calcium of whole blood transfusions.

They performed a retrospective review of data collected prospectively over a 2.5 year period on patients receiving whole blood. This included the number of transfusions, ionized calcium levels, and calcium replacements administered. Patients were divided into two groups, those who received whole blood only and those who were given whole blood and component therapy. Outcomes evaluated were ionized calcium levels, hypocalcemia correction, and death.

Here are the factoids:

  • During the study period, 335 patients received whole blood, but only 67% met inclusion criteria
  • About half (103) received a median of 2 units of whole blood (only!)
  • The authors do not state how many component units the whole blood plus component therapy group received
  • There was no difference in calcium levels based on average ISS in the two groups, although ISS does not differentiate injuries that bleed very well
  • Hypocalcemia occurred in only 4% of whole blood patients vs 15% of whole blood + components, which was significant
  • Hypocalcemia within the first hour was significantly associated with death in the first 24 hours and 30 days, although the standard deviation or SEM of this value was large
  • Whole blood only patients received less calcium replacement, and failure to correct was associated with 24 hour mortality
  • Median time to death in patients that “failed to correct” was 7.5 hours after admission

The authors conclude that hypocalcemia rarely occurs in whole blood only resuscitation, and that adding components increases its incidence and overall mortality. They state that aggressive calcium supplementation should be prioritized if component therapy is used.

Bottom line: There’s a lot to “unpack” here! Packed red cells are preserved with 3g of citrate per unit, whereas whole blood units contain only half that amount (1.66g to be exact). One would expect that one unit of packed cells would have twice the anticoagulant effect as a unit of whole blood.

This study is a blended model, where every patient got some whole blood, but some got components as well. Why? Is there a blood refrigerator in the ED stocked with whole blood, and when it is exhausted there is a switch to components? This model makes it more difficult to tease out the impact of the components given. Perhaps it could be done by matching patients with a given amount of whole blood. That is, comparing patients with 3 whole blood with those who received 3 whole blood + 2 PRBC.

There was no room in the abstract to explain why one third of patients were excluded from the study. This needs to be provided to ensure that the remaining two thirds are representative and can legitimately be analyzed. 

The number of units of whole blood per patient was low, with a median of two units given. Is it surprising that these patients did better than ones who received many more? Remember, from a citrate anticoagulant perspective, hanging two units of whole blood is the same as giving just one unit of PRBC.

This abstract raises a lot of questions, and the most important ones deal with how it was designed and the exact numbers of product given. Only then can we be confident that the rest of the associations described are significant.

Here are my questions for the authors and presenter:

  • Why did you choose the whole blood vs whole blood + components for your study? Wouldn’t it have been cleaner to do whole blood only vs components only? Perhaps all of your patients get whole blood? It seems like this might make the results more difficult to tease out.
  • How is whole blood made available for your trauma patients, and did this have an impact on your study? Do you have a limited number beyond which component therapy is used?
  • What were the inclusion criteria? These were not stated in the abstract, but a third of patients were excluded from the study based on them.
  • Could excluding a third of patients have skewed your results, and how?
  • How many component units were given along with the whole blood in the combination group? This was not provided in the abstract and will have a major impact on outcomes if the median total product numbers are significantly higher.
  • What does “failed to correct” mean? Were the patients not responding to large amounts of administered calcium, or were they not receiving large amounts of it?

I am very interested in the fine details in this abstract and will be listening intently to the presentation!


Best Of EAST #12: The Lasting Effect Of Trauma

Trauma professionals are keenly aware of the impact of traumatic injury on their patients. And they are particularly aware of the impact during their own phase of care. Prehospital providers know everything about the situation on scene and in their rig. Inpatient providers are experts in the trauma team activation process and other facets of inpatient care. Physiatrists excel at helping their patients overcome the immediate effects of injury.

But what happens later, three or six or more months down the road? A huge amount of data is collected during the acute care processes and maintained in local or national registries. But once the patient leaves the hospital, there is much less information available about long-term progress and outcomes.

The trauma group at the University of Pennsylvania examined longer-term physical, emotional, and social outcome information on their own patients over a two year period. They administered a set of test instruments and screens, including substance use, employment, living situation, PTSD, and PROMIS-29, a comprehensive evaluation of pain and seven health domains. This battery was given on admission, and then six months after discharge.

Here are the factoids:

  • A total of 618 patients underwent the initial screen, and 129 (21%) completed the six-month followup
  • Demographics of the pre- and post-followup groups were nearly identical
  • The incidence of penetrating trauma was high, about 25%
  • Half of patients had been previously hospitalized for an injury
  • There were statistically significant decreases in the ability to participate in social roles and activities, and a significant increase in anxiety and depression
  • PTSD was common, occurring in 28% of patients
  • Patients reporting only occasional employment or unemployment increased from 45% to 68%

The authors concluded that effects of injury extend beyond the initial pain and disability, impacting several areas for at least six months post-injury. They suggest that there is a need for screening and intervention protocols for post-injury patients.

Bottom line: This is an intriguing paper that focuses attention beyond the areas where most clinicians are aware. It points out the longer lasting impact from trauma, which may have a significant effect on the rest of the patient’s life. Any issues relating to mental or emotional health, or employment and livelihood may have a far ranging impact on that person’s life.

The sample size is small, and the attrition between initial interview and six month followup resulted in an even smaller analysis group. However, the similar demographics imply that the sample is reasonably valid. The screening tools were selected appropriately, and the statistical analyses seem to be appropriate.

This abstract points out the need to look beyond discharge to really find out how our patients are doing. We will probably not like what we see, and it should prompt us to develop more robust screening to figure out who is in trouble. Ultimately, this should move us to incorporate screening and appropriate interventions into the bigger trauma care picture, just as the authors suggest.

Here are my questions for the authors and presenter:

  • Are you confident that your data is representative of your patients given the steep attrition between admission and six month followup?
  • Can your results be generalized to other non-urban trauma patients? The number of patients suffering penetrating trauma or previously hospitalized for injury is very high. Might this group of patients suffer a disproportionately higher likelihood of disturbances at six months?
  • Although your screening test changes are statistically significant, are they clinically relevant? I have seen many numerically different results in other studies that have only questionable clinical significance (e.g. a decrease in ICU length length of stay of 0.4 days).
  • Has your work prompted you to design and implement the type of screening and interventions you are presenting?

This is important work, and will serve to increase awareness of the non-anatomic issues we absolutely must address in order to get our patients back to being healthy again.