Category Archives: Resuscitation

Head, Resuscitation

Best Of EAST #15: Prehospital TXA

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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.

Reference: THE EFFECTS OF TIMING OF PREHOSPITAL TRANEXAMIC ACID ON OUTCOMES AFTER TRAUMATIC BRAIN INJURY. EAST 35th ASA, oral abstract #40.

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Resuscitation

Best Of EAST #3: More Blood Product Stuff! Cryo vs Fibrinogen Concentrate

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I’ve got more blood transfusion stuff for you today! This one isn’t exactly MTP, but it does deal with patients suffering from blood loss. Major trauma patients requiring transfusion are losing all of their clotting factors in addition to red cells and platelets. Some factors can be replaced by giving plasma. However, clotting factor I (fibrinogen) is not one of them. For that reason, most MTPs include administration of cryoprecipitate to replace it at key points in the algorithm.

However, fibrinogen replacement actually is available in two forms, cryoprecipitate (cryo) and fibrinogen concentrate (FC). These two forms have very different properties and costs. The authors from the University of Arizona Tucson massaged two years worth of data from the TQIP database. They included all trauma patients who received either cryo or FC, except for those with known clotting issues from bleeding disorders, liver disease, or anticoagulants they were taking. They analyzed differences in mortality, complications, transfusion requirements, and length of stay.

Here are the factoids:

  • A total of 85 patients received FC and 170 received cryo (?)
  • Blood product usage (red cells, plasma, and platelets) was less in the fibrinogen concentrate group (see table)
  • ICU and hospital lengths of stay were less in the FC group (see table)
  • There was no difference in complications between the two groups

The authors concluded that use of fibrinogen concentrate was associated with improvement in the outcomes they measured. They recommended that further studies be done to evaluate use of FC.

Bottom line: This study suggests that use of fibrinogen concentrate may be better than cryoprecipitate. But there are a lot of things to think about before jumping to conclusions. First, remember that this is an association paper. It cannot detect cause and effect. Blood component usage and LOS were indeed less in the FC group. But how many hundreds of other variables factor into those outcomes: specific injury pattern, ISS, body temperature, resuscitation balance, time to OR, and product availability are just a few. These and a host of others cannot be controlled easily in a study using TQIP data alone.

Next, look at the number of units of blood products given as listed in the table above. These are the average number of units given within 24 hours! These are relatively low numbers, and below what most would consider a “massive transfusion” threshold. Most of the time, we wouldn’t even think to measure fibrinogen in patients with such low blood replacement needs. Perhaps we should?

And finally, I have questions about the low number of subjects in the study. There are only 255 patients analyzed, and propensity score matching was used. This implies that overall numbers were low and that several covariates had to be considered. It seems like more subjects should have been available in the tens of thousands of patients submitted in two years to TQIP

Here are my questions for the authors and presenters:

  • Please review your statistical analysis with the audience. Why is the number of subjects so low? What did you control for in your propensity score matching and how did this impact your n?
  • Comment on the low numbers of blood products given. Do you think that patients who have such a relatively low transfusion requirement even needed a fibrinogen supplement?
  • Did you consider performing this analysis on patients who underwent massive transfusion? The effect might have been more pronounced in that group.
  • Since fibrinogen concentrate costs about 3x what cryo does, how would this factor into the math involved in deciding to use FC?

This study raises a lot of interesting questions. I hope the authors incorporate the answers into their presentation!

Reference: FIBRINOGEN SUPPLEMENTATION FOR TRAUMA PATIENTS: SHOULD YOU CHOOSE FIBRINOGEN CONCENTRATE OVER CRYOPRECIPITATE? EAST 25th ASA, oral abstract #3.

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Best Of EAST #2: Pay Attention To Platelet Ratios In Your MTP!

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More MTP stuff! Every trauma center has a massive transfusion protocol, and current literature encourages them to try to achieve an “optimal” transfusion ratio. The literature has converged on a red cell to plasma ratio of somewhere between 1:1 and 2:1. Less has been written about platelet ratios, and trauma centers often don’t pay as much attention to this ratio when reviewing MTPs.

But is it important? The trauma group at the Massachusetts General Hospital examined the impact of platelet ratios on mortality in patients undergoing MTP. This was another TQIP data analysis, performed over a nine year period.

The authors defined massive transfusion as ten or more units of PRBC in the first 24 hours, or any number of units of red cells, plasma, or platelets given within the first four hours. They also defined “balanced” as a ratio of RBC to FFP and RBC to platelets <2. Multivariate regression analysis was performed to gauge the impact of ratios and achievement of a balanced resuscitation on 24-hour mortality.

Here are the factoids:

  • A total of 7,520 patients in the dataset underwent MTP
  • Nearly 83% achieved RBC to FFP balance, but only 6% had RBC to platelet balance (!)
  • Patients with both balanced FFP and platelets had the lowest mortality at 24 hours
  • Mortality increased by 2x with unbalanced plasma, a little more than 2x with unbalanced platelets, and 3x if both were out of balance (see figure)

The authors concluded that the platelet component of the MTP was frequently out of balance, and that it is associated with mortality to a greater degree than with unbalanced plasma.

Bottom line: This paper confirms my observations that trauma centers pay a lot more attention to the red cell to plasma ratio and don’t get as excited when the platelets are out of line. Part of this is probably due to confusion over how to count platelet packs. Typically they are delivered in packs called “pheresis” or “apheresis.” Each is the equivalent of about 6 units of platelets (check with your blood bank for more exact numbers). This means that a ratio of 6 RBC to 5 plasma to 1 platelets would be considered balanced. But a ratio of 28:28:2 would not.

According to this abstract, the use of sufficient platelets is important. This makes sense. However, the exact mechanism cannot be determined from this type of study. It could be a direct effect of not having enough platelets to form good clot. Or it could be something completely outside the clotting mechanism, just an association with something in the care processes that occurs as these patients undergo resuscitation. 

The why doesn’t matter so much, though. This abstract presents compelling data that suggests that we really need to pay attention to the platelet ratios given during the MTP. They should be analyzed just as closely as plasma ratios during PI review, and changes to the MTP process implemented to normalize this important ratio.

Here are my questions for the authors and presenter:

  • There is a statement in the methods section that is not clear. “only patients with steady RBC/PLT and RBC/FFP ratios between 4-and 24-hr were analyzed.” What is your definition of “steady?”
  • Did you see any mortality patterns in the data you analyzed that might suggest why lower platelet volumes were more deadly?

This was a nicely done abstract, and I look forward to the live presentation and the finished manuscript!

Reference: DON’T FORGET THE PLATELETS: BALANCED TRANSFUSION AND THE INDEPENDENT IMPACT OF RBC/PLT RATIO ON MORTALITY IN MASSIVELY TRANSFUSED TRAUMA PATIENTS. EAST 25th ASA, Oral abstract #1.

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Resuscitation

Best Of EAST #1: When Is MTP Blood Use Too Much?

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The 35th Annual Scientific Assembly of the Eastern Association for the Surgery of Trauma (EAST) begins in only a month! I will be there, sitting in the front row listening to all the great presentations. As usual, I have selected some of the abstracts that I find most interesting and will be sharing my thoughts on them with you over the coming weeks.

Let’s start out with a paper about the massive transfusion protocol (MTP). Blood has always been a scarce resource. And now, thanks to COVID, it is becoming even more so. Every trauma professional reading this has likely been involved in a trauma resuscitation that has used dozens of units of blood and other products. Unfortunately, most of the patients who require this much do not survive.

How does one balance the rapid use of many, many units of blood products with the (un)likelihood of survival and the impact of having less blood for other patients in your hospital or future incoming trauma patients? In other words, when does the use of additional blood become futile? Until now, there have been no real answers to these questions.

The trauma group at George Washington University did a deep dive into the TQIP database seeking some guidance on this topic. They reviewed five years of data, targeting patients who received at least one unit of blood within four hours of arrival. Four-hour and 24-hour mortality was analyzed to determine the point at which additional blood products did not improve survival.

The authors looked at the data two ways. They analyzed the results for all comers, as well as for patients who received balanced resuscitation. Balanced was defined as a red cell to plasma ratio in the range of 1:1 to 2:1. Results were controlled as best as possible for age, sex, race, highest AIS in each body region, comorbidities, advanced directives, and the type of surgery performed to control bleeding.

Here are the factoids:

  • Nearly 100,000 patient records were analyzed, and about 30,000 patients were found to have balanced resuscitation
  • In the all-comers group, mortality plateaued after 41 units at 4 hours and 53 units at 24 hours
  • In the balanced resuscitation patients, mortality plateaued at 40 units (4 hours) and 41 units (24 hours)

The authors concluded that this data should be used as markers for resuscitative timeouts to assess the plan of care.

My comments: This paper is very focused and provides some apparently straightforward results. However, it required some sophisticated statistical analysis to sift through the many variables that need to be controlled to obtain meaningful results. From reading the abstract, it appears that they did a good job of this.

I believe the lower number of units needed by 24 hours in the balanced resuscitation group demonstrates the benefit of getting the MTP ratios right. Non-balanced resuscitation is less efficient / effective and requires the use of more products to hit the mortality plateau.

This paper supports my opinion that a resuscitation timeout is a useful tool in helping us protect our valuable blood product resources and ensuring availability for as many patients in need as possible. What would this look like? Here are my thoughts:

  • Assign one person to monitor the MTP process in real-time. This obviously cannot be the surgeon or a member of the anesthesia team. Or even the operating room crew, as everyone will be very busy. The best practice I’ve seen is to have a dedicated trauma nurse or APP in the ED/OR recording the process on a specialized form and directing which units to give to keep the resuscitation balanced.
  • Call a timeout when the magic threshold is reached. This paper suggests that 40 is a good number.
  • Require that another trauma surgeon come into the room and review the patient condition, operative findings, and progress thus far. The two surgeons should then come to a consensus regarding utility vs futility of further surgery. Based on that decision, the operative procedure either continues or stops.
  • If the operation is to continue, then more timeouts should occur after a defined number of additional products are given.

Here are my questions for the authors / presenter:

  • The statistical analysis required is fairly advanced. Please explain in simple language why the specific regression analysis with bootstrapping was selected.
  • How do you envision applying the thresholds discovered in your paper?

This is an exciting paper and provides important information about the MTP process. I’m looking forward to hearing it in person!

Reference: CRESTING MORTALITY: DEFINING A PLATEAU IN ONGOING MASSIVE TRANSFUSION, EAST 25th ASA, oral abstract #14.

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Resuscitation

Are You A TXA Believer, Or TXA Hesitant?

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I’ve visited several hundred trauma centers over the past 25 years, and recently I’ve begun to appreciate that there are two camps when it comes to the use of tranexamic acid: the TXA believers and the TXA hesitant.

There have been a number of large studies that seem to suggest a benefit with respect to survival from major hemorrhage, particularly if given soon after injury (CRASH-2, MATTERs). This drug is dirt cheap and has been around a long time, so it has a clearly defined risk profile.

However, many of those hesitant to use it point to the possibility of thromboembolic events that have been sporadically reported. Several years ago, I did my own literature review and found that the number of thrombotic events from TXA was nearly identical to that of transfusing plasma.

JAMA Surgery just published a large systematic review, meta-analysis, and meta-regression that sought to examine the association between thromboembolic events (TE) in patients of any age and involving all medical disciplines, not just trauma.

The anesthesia group at the University Hospital Frankfurt in Germany did a systematic search of the Cochrane Central Register of Controlled Trials, as well as MEDLINE, for randomized controlled trials involving TXA. They covered all published studies through December 2020.

The authors adhered to standard guidelines for con-ducting reviews and meta-analysis (PRISMA). They specifically searched for outcomes involving TEs, such as venous thromboembolism, myocardial infarction or ischemia, limb ischemia, mesenteric thrombosis, and hepatic artery thrombosis. They also tallied the overall mortality, bleeding mortality, and non-bleeding mortality.

Here are the factoids:

• A total of 216 eligible trials were identified that included over 125,000 patients

• Total TEs in the TXA group were 1,020 (2.1%) vs 900 (2.0%) in the control group

• Studies at lowest risk for selection bias showed similar results

Bottom line: The authors concluded that IV TXA, irrespective of the dose, does not increase the risk of thromboembolic events. Period.

Hopefully, this is the final study needed to convince the TXA hesitant that it is safe to administer. They may still argue the efficacy, but at less than $100 per vial it is becoming impossible to ignore.

Reference: Association of Intravenous Tranexamic Acid
With Thromboembolic Events and Mortality A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery 156(6):3210884, 2021.

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