Tag Archives: whole blood

Best Of EAST 2023 #4: Whole Blood In Patients With Shock And TBI

We know that even a brief shock episode in patients with severe TBI dramatically increases mortality. Therefore, standard practice is to ensure good oxygenation with supplemental O2 and an adequate airway ASAP and to guard against hypotension with crystalloids and blood if needed.

Many papers (and several abstracts in this bunch) have been written about the benefits of whole blood transfusion. The group at the University of Texas in Houston compiled a prospective database of their experience with emergency release blood product usage in patients with hemorrhagic shock.

They massaged this database, analyzing a subset of patients with severe TBI, defined as AIS Head of 3. They specifically looked at mortality and outcome  differences between those who received whole blood and those who received component therapy.

Here are the factoids:

  • A total of 564 patients met the TBI + shock criteria, and 341 (60%) received whole blood
  • Patients receiving whole blood  had higher ISS (34 vs. 29), lower blood pressure (104 vs. 118), and higher lactate (4.3 vs. 3.6), all indicators of more severe injury
  • Initial univariate analysis did not identify any mortality difference, but using a weighted multivariate model teased out decreases in overall mortality, death from the TBI, and blood product usage
  • Neither statistical model demonstrated any difference in discharge disposition of ventilator days

The authors concluded that whole blood transfusion in patients with both hemorrhagic shock and TBI was associated with decreased mortality and blood product utilization.

Bottom line: This is yet another study trying to tease out the benefits of giving whole blood. The results are intriguing and show an association between whole blood use and survival. But remember, this type of study does not establish causality. It’s not possible to rule out other variables that were not available or not considered that could be the cause of the difference.

In this type of study, it’s essential to look at the design. Was it possible to create the study to record a complete set of variables that the researchers thought might contribute to the outcomes? Or is it a retrospective analysis of someone else’s data that contains just a few of them? This study falls into the latter category, so we have fewer data elements to work with and the likelihood that others that are not present could contribute to the outcomes.

The details of the multivariate analysis are also important. The authors stated that weighted multivariate analyses were performed. It’s not possible to provide details in a standard abstract, but these will be important for the audience to understand.

Here are my questions and comments for the presenter/authors:

  • Tell us more about the database you used for the analysis. What was the purpose? How many data elements did you collect, and how are they related to your research questions?
  • How did you decide which variables to include in your multivariate analysis? And how did you determine the weights? These can have a significant effect on your results.
  • This is a preliminary proof of idea study. How should this be followed up to move from association to causation?

This is just one of many exciting studies trying to shed light on the forgotten benefits of whole blood in trauma. I’m looking forward to seeing the final manuscript!

Reference:  PATIENTS WITH BOTH TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK BENEFIT FROM RESUSCITATION WITH WHOLE BLOOD. EAST 2023 Podium paper #2.

Best Of EAST 2023 #3: The Cost Of Whole Blood vs Component Therapy

Decades ago, blood banks discovered they could fractionate units of whole blood into components for focused use. This was useful for patients who were thrombocytopenic or needed specific plasma factors. But trauma patients bleed whole blood, and trying to reassemble whole blood from components does not work well. Have a look at this chart:

It all comes down to money. Blood banks found they could charge more for the sum of the components of a unit of whole blood rather than the one unit itself. But now, with whole blood in trauma becoming a thing again, it’s essential to reexamine costs.

The University of Texas at San Antonio group examined transfusion-related charges for trauma patients receiving either component therapy or low-titer O+ whole blood within six hours of arrival. This was a retrospective review of prospectively collected data. During the first two years, only component therapy was given. Whole blood was introduced during the last four years.

Here are the factoids:

  • Once the trauma center switched to whole blood, total annual transfusion charges, as well as component charges decreased by 17% overall
  • In both adults and children, whole blood was associated with a significantly lower cost per ml delivered and cost per patient throughout all phases of care
  • In severely injured patients (ISS>15), the same significantly lower costs were also noted
  • Patients who triggered the massive transfusion protocol also had a lower cost per ml of product in the ED and the first 24 hours

The authors concluded that whole blood was associated with lower charges and “improved logistics,” especially in massive transfusion patients.

Bottom line: This is an interesting and important paper. However, several questions still need to be answered. I recognize that there is limited space in an abstract, so I will list them below in hopes the authors will answer them during the presentation.

The first issue is that the numbers of patients and quantities of blood products given need to be listed. These are very important because the figures list only total charges and maybe costs. These numbers are not per unit of product, so the data may be skewed if the number of patients was different between the groups. For example, if 100 patients received component therapy and only 10 got whole blood, costs or charges could definitely be skewed.

And then there is the cost vs. charge confusion. The abstract seems to use them interchangeably. The methods section of the abstract states that charges were analyzed. Yet cost is mentioned in the results, and figure two shows “cost” on the axes, but the caption states that charges were listed. 

We all know that hospitals can charge whatever they like, and that amount may vary based on insurance and other factors. The relationship between the charge and the cost is tenuous at best. Hopefully, the authors will clarify this at the start of the presentation.

Here are my comments and questions for the presenter/authors:

  • Please clarify the concept of charges vs. costs at the presentation’s beginning. If you truly analyzed only charges, do they bear any relationship to the actual costs of the units?
  • Shouldn’t your analysis of annual “charges” for product expenditures in Figure 1 be per unit? Otherwise, the costs and charges could be lower if fewer products were given after whole blood was introduced.
  • Was the switch to whole blood absolute, or was component therapy still given in some cases after 2018? If the switch was not total, there could be a selection bias in patients who received whole blood.
  • Figure 2 also appears to be total charges (or costs), not per patient or unit. But, again, without numbers it is difficult to say if the dollar differences are significant.
  • What are the “improved logistics” mentioned in the conclusion section? And how could they lower charges (or costs) in your study?

Lots of questions. I think you will need to provide a lot of explanation up front to justify your findings. Nevertheless, I’m excited about the presentation.

Reference: TRANSFUSION-RELATED COST COMPARISON OF TRAUMA PATIENTS RECEIVING WHOLE BLOOD VERSUS COMPONENT THERAPY. EAST 2023 podium abstract #28.

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!

Reference: WHOLE BLOOD RESUSCITATION IN TRAUMA REGULATES CALCIUM HOMEOSTASIS AND MINIMIZES SEVERE HYPOCALCEMIA SEEN WITH COMPONENT THERAPY. EAST 35th ASA, oral abstract #6.

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.

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.