Category Archives: Resuscitation

Best Of The AAST #7: TXA And Thromboembolism

The use of tranexamic acid (TXA) in trauma patients has escalated dramatically since the CRASH-2 trial was published ten years ago. It has become a frequent addition to the massive transfusion protocols used by trauma centers. And we are now even seeing TXA given by prehospital provides when life-threatening bleeding is suspected.

This drug is popular because it is inexpensive (~$100/dose) and is thought to be safe. However, some trauma professionals have been concerned about thrombotic side effects since TXA is a finbrinolysis inhibitor.

The group at the Mayo Clinic performed a retrospective study of seven years of their own data to determine if the concern for thrombotic complications was warranted. They specifically evaluated in-hospital mortality and thrombotic events up to 28 days after injury.  They also scrutinized outcomes in patients who received only the bolus TXA injection, but not the infusion.

Here are the factoids:

  • A total of 848 patients were included in the study, but there was no information as to what the inclusion criteria were
  • Only 212 received TXA; the other 636 were considered the control group, and there were no differences in age, sex or mechanism of injury
  • Thrombotic events occurred in 13% of the TXA patients and only 6% in the control group, which was statistically significant
  • Specific thrombotic events in TXA vs non-TXA patients: DVT was 8.5% vs 3.5% (significant), pulmonary embolism was 3.8% vs 1.9% (NS), MI was 1.9 vs 0.4% (NS), stroke was 2.4% vs 1.1% (NS)
  • Thrombotic events occurred more frequently in patients who received both doses of TXA (23%) vs just the bolus (10%), and this was also significant
  • In-hospital mortality was 21% with TXA vs 10%, which was not significantly different, controlling for confounders

The authors concluded that TXA administration was associated with higher rates of thrombotic events. They went on to state that TXA should not be routinely given for trauma patients in the community setting.

Here are my comments:

This is a bold recommendation from this very small study. The CRASH-2 trial was randomized and placebo controlled, and analyzed their experience with 10,000 subjects in each arm. This retrospective study has only  212 TXA vs 636 control patients. Big difference.

The authors attempt to match the TXA patients with controls. They controlled for age, sex, mechanism, and ISS. But it does not appear that there was any control for injuries known to increase the risk of thrombotic events like spine and pelvic fractures.

And why look at a full 28 day interval for thrombotic events? I would expect most of these events to occur in the first few days. Including an entire month in the study allows thrombotic events from other causes to creep in.

Here are some questions for the presenter and authors:

  • Please comment on how the small numbers in your study may have an impact on the results.
  • What were the selection criteria for your 848 patients? Were they all of your trauma activation patients? If not, is there some selection bias possible?
  • DVT appears to be the driver for your “significant” number of thrombotic events. Yet the other events (MI, stroke, PE) were not significantly different. This seems counter-intuitive, since the DVT numbers themselves numbered only about 20 in each group. Please describe the statistics you used to derive this conclusion.
  • Did you look at the incidence of injuries that are known to increase the risk of thrombotic events in the two groups? If there was an excess of pelvic or spine fractures in the TXA group, this might not be picked up in your analyses and could skew your data.
  • Why did you include thrombotic events for a full 28 days after injury? This allows for later events caused by factors other than the TXA. Show us a redo of your analysis using 5 or 7 day thrombotic events.

These are interesting numbers, but I have to admit that I am skeptical. I’m not clear how community hospital administration of TXA makes it more likely associated with thrombotic events. I will definitely be listening intently to this presentation. And probably asking these questions.

Reference: Risk of thromboembolic events after the use of TXA in trauma patients. AAST 2020, Oral Abstract #15.

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Best of AAST #1: What Has The MTP Bought Us?

Let’s kick off my reviews of AAST 2020 abstracts with a paper on the results of recent advances in hemorrhage control. Over the past 10+ years we have seen the following new (and old) tools move into more widespread use:

  • Massive transfusion protocol (MTP) with a goal of 1:1 ratios of red cells to plasma
  • Availability of liquid plasma for more rapid use in the MTP
  • Addition of tranexamic acid (TXA) to resuscitation
  • Resurgence of tourniquet use by prehospital providers
  • Adoption of REBOA and TEG
  • Transfusion with whole blood

The authors analyzed their experience after serially introducing these tools to their resuscitation strategies, and studied their impact on overall mortality.

They retrospectively reviewed the experience over a 12 year period at their large Level I trauma center. Here are the factoids:

  • The reviewed a total of 824 MTP events. To put this into perspective from a volume standpoint, this is a little over one MTP activation per week.
  • Patients were primarily young (median age 31), male (81%), with a penetrating mechanism (68%). Median ISS was 25
  • Prehospital times were significantly longer at the end of the study, but the authors state that there was no correlation with an increase in in-hospital mortality
  • During the entire study, overall mortality ranged from 38% to 57%, and logistic regression did not identify an effect from any of the interventions

The authors concluded that their mortality rates have not improved despite all of the advancements we have added over the past decade. They suggest that future efforts should attempt to move targeted hemorrhage control backwards in time, out of the ED and toward to injury scene.

Here are my comments: This is an interesting and simple-appearing study. Overall, the authors didn’t really show that any of our “modern” resuscitation interventions did much for their patients at all.  There was a suggestion that tourniquet implementation and use of whole blood tended toward improving things.

But don’t be fooled by simplicity. There are many, many factors that enter into whether an individual patient lives or dies. When you fail to see a significant result in a study, first look at the methods and tools used for measurement. Are they powerful enough to discern changes? Do they cover enough of the factors that promote survival, not just our resuscitative advances? Or is the tool looking at the wrong things?

One big difference at this center is the sheer volume of penetrating trauma. This could have a major impact on survival, and may be very different from the experience of most centers that have predominantly blunt injury mechanisms.

And some questions for the authors:

  • What exactly is your definition of mortality? Made it out of the ED? Lived twenty four hours? Thirty days? This makes a big difference in how you look at the results.
  • Since you have only about one MTP event per week, do you think your numbers are large enough to actually detect a mortality difference? 
  • Did you consider looking at your unexpected survivors to see if there were any common threads in their care that might have made the difference? Maybe some of our resuscitative advances do make a difference, but only in specific subsets of patients.
  • Can you speculate about the reasons for longer prehospital times, and the impact on mortality?
  • How would you recommend pushing hemorrhage control back toward the scene? New tools for prehospital providers? More advanced providers in the rigs? This is an intriguing concept and it would be interesting to hear your thoughts.

This is a thought provoking paper that questions our assumptions about our time-honored resuscitation tools. I look forward to hearing it live next month!

Reference: After 800 MTP events, mortality due to hemorrhagic shock remains higha nd unchanged despite several hemorrhage control advancements; is it time to move the pendulum? AAST 2020 Oral Abstract #1.

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Giving TXA Via An Intraosseous Line?

Seriously injured patients frequently develop coagulopathy, which makes resuscitation (and survival) more challenging. A few years ago, the CRASH-2 study lent support for using tranexamic acid (TXA) in select trauma patients to improve survival. This drug is cheap and has antifibrinolytic properties that may be beneficial if given for life-threatening bleeding within 3 hours of initial injury. It’s typically given as a rapid IV infusion, followed by a slower followup infusion. The US military has adopted its routine use at forward combat hospitals.

But what if you don’t have IV access? This can and does occur with military type injuries. Surgeons at Madigan Army Medical Center in Washington state tried using a common alternative access device, the intraosseous needle, to see if the results were equivalent. This study used an adult swine model with hemorrhage and aortic crossclamping to simulate military injury and resuscitation. Half of the animals then received IV TXA, the other half had it administered via IO. Only the bolus dose was given. Serum TXA levels were monitored, and serial ROTEM determinations were performed to evaluate coagulopathy.

Here are the factoids:

  • The serum TXA peak and taper curves were similar. The IV peak was higher than IO and approached statistical significance (0.053)
  • ROTEM showed that the animals were significantly hyperfibrinolytic after injury, but rapidly corrected after administration of TXA. Results were the same for both IV and IO groups.

Bottom line: This was a very simple and elegant study. The usual animal study issues come into play (small numbers, pigs are not people). But it would be nearly impossible to have such a study approved in humans. Even though the peak TXA concentration via IO is (nearly significantly) lower, this doesn’t appear to matter. The anti-fibrinolytic effect was very similar according to ROTEM analysis.

From a practical standpoint, I’m not recommending that we start giving TXA via IO in civilian practice. We don’t typically see military style injuries, and are usually able to establish some type of IV access within a reasonably short period of time. But for our military colleagues, this could be a very valuable tool!

Reference: No intravenous access, no problem: Intraosseous administration of tranexamic acid is as effective as intravenous in a porcine hemorrhage model. J Trauma 84(2):379-385, 2018.

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Massive Transfusion: What’s The Right Ratio?

In my last post, I analyzed a survey that studied the massive transfusion protocol (MTP) practices of academic Level I trauma centers in the US. What centers do is one thing. But what does the literature actually support? A group from Monash University in Melbourne, Australia and the National Health Service in the UK teamed up to review the literature available through 2016 regarding optimal dose, timing, and ratio of products given during MTP.

One would think that this was easy. However, the search for high quality ran into the usual roadblock: the fact that there is not very much of it. The authors scanned MEDLINE for randomized, controlled studies on this topic, and found very few of them. Out of 131 articles that were eligible, only 16 were found to be suitable for inclusion, and 10 of them were still in progress. And only three specifically dealt with the ratio question. Even they  were difficult to compare in a strict apples to apples fashion.

Here are the factoids that could be gleaned from them:

  • There was no difference in 24-hour or 30-day mortality between a ratio of 1:1:1 (FFP:platelets:RBC) vs 1:1:2
  • However, a significantly higher number of patients  achieved hemostasis in the 1:1:1 group (86% vs 78%)
  • There was no difference in morbidity or transfusion reactions in the two groups
  • One study compared 1:1 component therapy with whole blood transfusion and found no difference in short-term or long-term mortality or morbidity

Bottom line: As usual, the quality of available data is poor if one limits the field to randomized, controlled studies. Ratios of 1:1:1 and 1:1:2 appear to be equally effective given the limited information available. A number of papers not included in this review (because of their less rigorous design) do seem to indicate that higher ratios of RBC (1:3-4) appear to be detrimental. And as time passes, more and hopefully better studies will be published.

What does this all mean for your MTP? Basically, we still don’t know the best ratio. However, it is recommended that your final ratios of FFP:RBC end up somewhere between 1:1 and 1:2. The only way to ensure this is to set up your MTP coolers so the the ratio of product they contain is better than 1:2. This means more plasma than 1 unit per 2 units of red cells. 

If you set it at the outside limit of 1:2, then that is the best ratio you can ever get assuming everything goes perfectly. However, if you have to thaw frozen plasma, use too much emergency release PRBC before activating MTP, or someone cherry-picks the coolers to transfuse what they think the patient needs, the ratios will quickly exceed this boundary.

So be sure to load your coolers with ratios that are closer to 1:1 to ensure that your final ratios once MTP is complete are what you want them to be. And monitor the final numbers of every one of your MTP activations through your trauma performance improvement program so you know what your patients are really receiving.

Reference: Optimal Dose, Timing and Ratio of Blood Products in Massive
Transfusion: Results from a Systematic Review. Transfusion Med Reviews 32:6-15, 2018.

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AAST 2019 #1: Survival Benefit Of Pelvic REBOA

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is one of the new, shiny toys in the trauma professional’s toy chest. Research papers on the topic are increasing exponentially, but human data was not even published until 2014! This is still a new device and we are trying to learn more about it.

The AAST set up an Aortic Occlusion for Resuscitation in Trauma and Acute Care (acronym is AORTA, ugh!) to help accumulate data for this not-often used technique. Hopefully, compiling comprehensive use and outcome data will speed our appreciation of the usefulness of this device.

A multi-institutional trauma group massaged the AORTA registry to examine the potential benefits of using the technique in patients with pelvic fractures leading to severe blood loss. They specifically looked for patients with the balloon inflated in Zone 3 to decrease bleeding from below the aortic bifurcation. Here’s a diagram of the zones:

The authors identified a total of 109 patients pelvic fractures with bleeding from below the bifurcation.

Here are the factoids:

  • The presenting patients arriving without CPR all had similar base deficit, lactate, and systolic BP. This shows us that the two groups are the same, but only for these three parameters. GCS was lower in the open aortic occlusion group. This could certainly contribute to a higher overall mortality in this group.
  • Overall mortality was significantly lower in the REBOA group that included those arriving with CPR in progress (35% vs 80% for open occlusion)
  • And when CPR patients were excluded, the mortality was significantly lower (33% vs 69%)
  • One in ten patients undergoing REBOA suffered vascular access complications (vascular repair required, limb ischemia, distal embolization, or amputation)
  • Complications among survivors were not different between the groups, nor were hospital or ICU lengths of stay or blood usage

The authors state that their data shows a “clear survival advantage” in those patients who undergo REBOA. Furthermore, this was accomplished without increasing systemic complications. They finally conclude that REBOA should be “strongly considered” for patients in shock due to pelvic trauma.

Not quite so fast here. There are several more factors in play than meet the eye.

First, a study that massages a REBOA database was generally constructed to see if REBOA is beneficial, especially in this time of rapid investigation. And it was performed by institutions who are using it regularly. This could introduce a significant degree of confirmation bias, since we all try to see what we already believe to be true (“REBOA is good”).

The authors are basing this “clear survival advantage” on overall mortality where only a few confounding factors have been controlled for. The GCS wild-card here is a perfect example. It could have considerably contributed to mortality in the open group, making it look bad. Who determined whether REBOA or open technique would be used, and why? This can have a major impact. What other factors might be present that are not even recorded in the database?

It is also stated that this increased survival was accomplished without increasing systemic complications. Perhaps, but that may be true of only the ones examined, or those recorded in the registry. Many may be missing. And what about the 10% incidence of limb issues in the REBOA group? This is a major problem and should not be glossed over. Although the patients that required a vascular repair were reported to do well, the others with ischemia or limb loss obviously did not.

Bottom line: Reading abstracts is like reading scientific papers, only more difficult because information is missing due to length limitations. Look at the title. Look at the conclusions. But don’t believe anything until you can understand every one of the results listed. And be sure to think about all the things that have to be left unsaid because of the size of the abstract! 

Having said all that, I still have to be careful that this doesn’t trigger my own confirmation bias. My take is that REBOA is still an investigational device. We need further comprehensive data to make sure that survival and safety are properly balanced.

Here are some questions for the presenter and authors:

  • The abstract describes the number of cases identified as 109; 84 REBOA and 25 open occlusions of the aorta. This seems to include patients undergoing CPR upon arrival, and these are excluded from some of the statistics. However, I can’t get the mortality percentages to match for the group that supposedly includes CPR patients. For example, the overall REBOA (includes CPR) mortality percentage is 35.17%. Multiplying this by 84 gives 29.5 patients. But multiplying the 33.33% mortality (CPR-excluded group) by 84 yields 28 patients. So are the 109 patients listed in the abstract the CPR-excluded group or not?
  • The open aortic occlusion group had a lower GCS. Did you look at how this might have contributed to the higher observed mortality? Although numbers are already low, is there any way to match for this to clarify the picture?
  • Do you have any information yet on longer term outcomes in the two groups? This will become very important as we come to balance raw survival with quality of life and complications.

Great abstract! I’m looking forward to the presentation, and hopefully more answers!

Reference: SURVIVAL BENEFIT FOR PELVIC TRAUMA PATIENTS UNDERGOING RESUSCITATIVE ENDOVASCULAR BALLOON OCCLUSION OF THE AORTA: RESULTS OF AAST, AORTIC OCCLUSION FOR RESUSCITATION IN TRAUMA AND ACUTE CARE SURGERY (AORTA) REGISTRY. AAST 2019 Oral Abstract #3.

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