Category Archives: Resuscitation

Are You A TXA Believer, Or TXA Hesitant?

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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Best Of AAST 2021: Are We Getting Better At Balanced Resuscitation?

The way we resuscitate major trauma patients has been changing over the past decade. Even the 10th edition of the ATLS course has recognized that so-called balanced resuscitation is important. This concept limits the use of crystalloid and relies more heavily on blood component administration in ratios that more closely approximate whole blood.  Balanced resuscitation typically translates as the use of less than two liters of crystalloid, and blood product transfusion ratios of 1:1 to 2:1 (PRBC to plasma).

We have also recognized the critical importance of rapid control of major hemorrhage, which is best accomplished in an operating room.  The group at the University of Arizona massaged the TQIP database to see if these changes are having a significant impact on our patients.

They looked at five years worth of data, specifically reviewing information on adult patients with both transfusion and laparotomy occurring within four hours of arrival. The authors performed regression analyses to identify trends over the study period.

Here are the factoids:

  • Nearly 10,000 patients met study criteria with a mean age of 44 and ISS 34
  • Patients were in shock, with mean SBP 78 and median number of transfusions of 9 PRBC and 6 plasma
  • Time to laparotomy decreased from 1.87 hours to 1.37 hours over the five year period
  • 24-hour mortality decreased from 23% to 19% during the study
  • Blood product ratio decreased from 1.93:1 to 1.73:1
  • The authors state that the blood product ratio was independently associated with 24 hour mortality (odds ratio of 1.09) and in-hospital mortality (1.10) (??)

The authors conclude that resuscitation is becoming more balanced and time to surgery shorter, with a significant improvement in mortality.

Bottom line: Well, this is an interested study of associations. It uses a large database, which of course limits some of the information available. There are obvious trends toward faster time to OR (by 30 minutes) and a 4% improvement in survival. But the transfusion ratio really looks to be about the same. 

Let’s do the math, assuming that an average of 10 units of PRBC were given. A ratio of 1.93 would mean that 5.2 units of plasma were give (1425 cc, assuming 275 cc per unit). The ratio of 1.73 noted in 2017 would then be 5.8 units, or 1590 cc. This is an increase in FFP transfusion of 165 cc.

The authors stated that the improvement in transfusion ratios was statistically associated with the improvement in survival. I think this is one of those situations where there is a big difference between statistical significance and clinical significance. Do you really think that giving just 165 additional ccs of plasma could have that much overall effect on survival?

My suspicion is that there is a true association between the more rapid time to OR (and presumably surgical control) and survival. It’s just that the numbers were not clean enough to meet statistical rigor.

This is an interesting abstract, and shows that we are slowly getting better at controlling bleeding. But I think the most important takeaway is that we are not as good at balanced resuscitation as we think we are. We seem to be hovering at the 2:1 ratio, and only very slowly moving toward 1:1.

Questions for the authors / presenter:

  • Were you able to see a correlation between time to OR and survival?
  • Please comment on the association between transfusion ratios and survival, especially given the very small change over time.
  • Please clarify the in-hospital mortality and 24-hour mortality variables. In-hospital mortality suddenly pops up at the end of the results, but was never mentioned before.

Reference: AFTER 9,000 LAPAROTOMIES FOR BLUNT TRAUMA, RESUSCITATION IS BECOMING MORE BALANCED AND TIME TO INTERVENTION SHORTER: HOW LOW CAN WE GO? AAST 2021, Oral abstract #3.

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Best of EAST #7: Whole Blood Plus 4-Factor Prothrombin Complex Concentrate

In my last post, I went through some of the basics of whole blood transfusion. However, the focus was more on compatibility than function. Today, I’ll review an abstract that explored functionality of that blood transfused.

In theory, whole blood contains the usual array of clotting factors. It has been shown that high factor levels persist in whole blood, even when stored at room temperature. So in theory, additional clotting factor infusion should not be necessary.

The group at the University of Arizona explored adding 4-factor prothrombin complex concentrate (4-PCC) to whole blood transfusion. The scanned three years of data in the TQIP database. They identified two groups of patients, those who received whole blood alone and those who received 4-PCC in addition to it. They were interested in the impact on total product transfused and the usual crude outcomes of hospital / ICU length of stay and mortality.

Here are the factoids:

  • Only 252 patients in this entire database (tens of thousands of records in three years) received whole blood, and 84 of them also received 4-PCC
  • The patients tended to be young (average age 47), 63% male, with moderate (median ISS 27), and blunt injury in 85%
  • Administration of 4-PCC was associated with a significantly decreased transfusion requirement of both blood (5 vs 8 units) and plasma (3 vs 6 units), but not platelets
  • ICU LOS was significantly lower in the 4-PCC group (5 vs 8 days), but there was no difference in hospital stay or in-hospital mortality

The authors concluded that 4-PCC given with whole blood was associated with a decrease in transfusion requirements and ICU length of stay, and that further studies were needed.

My comments: Well, this is certainly interesting and unexpected.  Why would a clinician even think of giving 4-PCC when giving whole blood? It looks like a very rare occurrence in the dataset. Unfortunately, we can never find out. We can’t just go back and look in the charts. Perhaps these centers were using TEG or ROTEM during the resuscitation?

As always in these big databank analyses, the researchers can only control for the variables they can think of that are already present in the database. Although they were able to match the patient groups for the usual demographics, vital signs, injury patterns, comorbidities, and trauma center level, it is entirely possible that there were other factors in play.

Here are some questions for the authors and presenter:

  • Why did you choose to do this study? Was there some clinical question that arose that triggered it? Something you found in the literature that suggested it?
  • How do you explain the results, given that the factors in 4-PCC have been shown to persist at functional levels in whole blood? Why do you think less blood and plasma were needed?
  • What needs to happen next? I agree that more research is needed to see if this association is real. How would you go about doing it?

Thanks for a very intriguing paper! Details will follow, I’m sure.

Reference: Four factor prothrombin complex concentrate in adjunct to whole blood in trauma-related hemorrhage: does whole blood replace the need of factors? EAST 2021, Paper 18.

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Best of EAST #6: Does Rh Status Matter In Whole Blood Transfusion?

What goes around comes around. Fifty plus years ago, the only transfusion product available was whole blood. Then the major blood banks discovered that more patients could be treated for specific problems if the blood were fractionated. Packed red cells then became the standard for trauma transfusion and persists to this day.

But there is a move afoot to re-explore the use of whole blood. There are many theoretical advantages, since our trauma patients are bleeding whole blood, not packed cells. Unfortunately, combining a unit of packed red cells, plasma, and platelets does not give you a reconstituted unit of whole blood by a long shot. Check out this diagram:

The challenge is that we are used to only thinking about universal donor red cells (group O Rh-). This is the safest packed cell product to give a patient with an unknown blood type. But unfortunately, it is also one of the hardest to find, present in about 7% of the population.

Packed red cells are nearly plasma free. What we don’t think about with whole blood is the level of antibodies to blood groups that are present in the plasma. Group O blood will have plasma with anti-A and anti-B antibodies. So if we include the plasma with those universal donor red cells, these antibodies may attack the patient’s red cells if he or she is group A, B, or AB and cause a reaction.

Theoretically, this issue can be avoided by using universal donor plasma (group AB+). Since the donor has all of the major group antigens, they will have no antibodies in their plasma. Unfortunately again, this is a rare type and tough to get donors (about 3% of the population).

To avoid potential transfusion reactions, group O whole blood is tested for antibody titers, and only low titer blood is selected for transfusion. Typically Rh- whole blood has been selected to avoid any issues with Rh incompatibility, even though reactions to this antigen are usually mild.

The group at the University of Texas – Houston reviewed their experience using Rh+ low titer group O blood in trauma resuscitations. Their two-year study substituted Rh+ whole blood when Rh- product was not available. They monitored patients for transfusion reactions, renal failure, sepsis, VTE, and ARDS.

Here are the factoids:

  • A total of 637 patients received low titer group O blood during the study period; 448 received Rh+ product and 189 received Rh-
  • Those receiving Rh+ blood were more likely to be male, had lower initial SBP, and a significantly lower GCS (7 vs 12)
  • Overall there were no differences in hemolysis labs, transfusion reaction, complications or mortality
  • The patient groups were then sliced and diced by their own Rh antibody status to see if Rh- patients had an increased likelihood of problems from Rh+ plasma
  • Once again, the Rh- subgroup was significantly different for sex (57% female vs 26% in the Rh+ group), and blunt trauma mechanism (92% vs 70%)
  • And once again no differences were seen in hemolysis, transfusion reaction, complications or mortality

The authors then concluded that Rh+ low titer whole blood is a safe alternative in either Rh+ or Rh- patients.

My comments: Sounds good, right? But wait a minute! This was a non-randomized observational study. It appears that Rh+ whole blood was used when Rh- was unavailable, which was quite a bit of the time. This is clear when you see the demographic differences listed above between the two recipient groups, as well as the subgroups stratified by their own Rh status.

This is the first thing that makes me a bit more skeptical of the recommendation. The other one is something you’ve heard me harp about before… non-inferiority studies. This abstract tries to say that since they did not detect a difference, then the two products are equivalent.

That is only true if there is adequate power in the number of patients studied. If not, you may not be able to show a statistically significant difference. By my own calculations, if the incidence of transfusion reaction in the Rh- group is 1% and the ratio of the patient groups is 0.42, the reported sample size could only show a significant difference if the Rh+ patients had a 5% transfusion reaction rate.

So is it truly non-inferior, or does the study need include a lot more patients? 

Here are my questions for the authors and presenter:

  • What is the impact of the non-randomized patient selection process on your results? The groups and subgroups appear to be very different. Couldn’t this influence your results?
  • Exactly what type of statistical analysis did you use? Your abstract merely lists the software package, not the specific tests applied.
  • Do you believe that your study is sufficiently powered? What assumptions did you use to calculate this?

As we move toward more use of whole blood, the Rh question will be an important one. I look forward to questioning the authors on this one!

Reference: Can Rh+ whole blood be safely used as an alternative to Rh- product? An analysis of efforts to improve the sustainability of a hospital’s low titer group O whole blood program. EAST 2021, Paper 17.

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Best of EAST #2: Blood Transfusion And Nosocomial Infection

This abstract falls into the “interesting, but how can we use this bit of information” category. We’ve known that transfusing packed red cells raises nosocomial infection rates for at least 15 years. The group led by MetroHealth in Cleveland combined forces with the Vanderbilt trauma group to re-look at their data from the PAMPer trial with respect to trauma patients.

The PAMPer trial (Prehospital Air Medical Plasma) examined the effect of tranfusion of two units of plasma in the air ambulance on mortality, transfusion need, and complications. Half of the patients got plasma plus standard care, and the other half standard care alone.

This abstract uses PAMPer trial data to examine the impact of giving any amount of blood on nosocomial infection in these patients. These infections included pneumonia, bloodstream infection, C Diff colitis, empyema, and complex intra-abdominal infection.

The group retrospectively analyzed the prospectively collected PAMPer data and used logistic regression models to test for an association.

Here are the factoids:

  • A total of 399 patients with the usual trauma demographics were included (younger male, moderately injured, blunt mechanism)
  • Ten percent of patients died, and 23% developed nosocomial infections
  • Pneumonia was by far the most common complication (n=67) with all others in the low teens or below
  • Although only two thirds of patients received plasma, 80% were given PRBCs and 27% received platelets
  • Patients who received any amount of packed cells had a 2.3x increase in nosocomial infections, and the number given increased the rate of nosocomial infection (1.06x)

The authors concluded that patients in the PAMPer trial who received at least one unit of blood “incurred a two-fold increased risk of nosocomial infection” and that this risk was dose dependent.

My analysis: The biggest obstacle for me to buy into this work is the enrolled patient group. Studies in which you borrow someone else’s data are always a bit problematic. You have no control over the variables, as they’ve been determined by someone else.

In this case, the dataset could only be controlled for age, sex, and ISS. But what about all the other stuff that might have an impact on infections? Things like pulmonary injury, the 20% of patients who had penetrating injury, and severe TBI patients with their propensity to develop VAP.

The odds ratios of the associations were a bit on the low side. Sure, the overall nosocomial infection odds ratio was 2.37 but the confidence interval was 1.14 to 4.94. This is very wide and it means that the odds could have been anywhere from 1.14x to almost 5x. This suggests that the study group may not have been large enough to give us a clear picture. And the odds ratio for number of PRBC units vs infection was only 1.06 with a tighter confidence interval. So even if it is present, this association is very, very weak. I like to see ridiculously large odds ratios when reviewing observational studies like this where the input data is constrained.

My final comment on this study deals with its utility. These are trauma patients. They are bleeding. We’ve known that transfusions may increase the nosocomial infection rate in critically ill patients for at least 15 years. But we will still have to give the patients blood. So what are we to do?

Here are some questions for the authors and presenter:

  • Please comment on the limitations you faced using the PAMPer dataset. Were you satisfied with the range of variables available? Which additional ones would you have liked to work with?
  • Do you feel that the 399 patients provided enough statistical power for analysis? The confidence intervals are large and very close to the OR=1 line.
  • What should we do with your conclusions? Can we translate this into clinical practice?

One final note: the patients did not “incur increased risk.” Rather, there was an association with increased risk of infection. We really don’t know if it was from the blood or something else that was not recorded in the PAMPer dataset.

Reference: Dose-dependent association between blood transfusion and nosocomial infections in trauma patients: a secondary analysis of patients from the PAMPer trial. EAST 2021, Paper 3.

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