Tag Archives: whole blood

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.

Best Of EAST #10: MTP With Whole Blood

Here’s one last abstract to consider before the EAST meeting kicks off this afternoon. Every trauma center must have a massive transfusion protocol (MTP). But not every one has access to whole blood. And whole blood is all the rage now for transfusion in the trauma world.

Believe it or not, we must still ask the question “is using whole blood safe?” More than 50 years ago, all we had was whole blood. But we didn’t use it in trauma the way we do today. And we didn’t have the tools then to determine whether there were any adverse effects from its use. Now we do, and we are slowly rediscovering the nuances of using it. Some work has shown that small volumes of whole blood appear to be safe. But there is little information on the safety of using large volumes in MTP.

The group at Oregon Health Sciences University in Portland attempted to do this with a quick shot paper to be presented tomorrow morning. They reviewed their experience over a two year period. For the first 18 months, they used standard component therapy (PRBC + plasma + platelets) in their MTP. For the final six months, they used cold-stored uncrossmatched, low-titer group O blood. Any patient who had MTP activated and received even a single unit of blood was included in the study. 

Here are the factoids:

  • 83 patients received component therapy and 42 received whole blood; demographics were the same
  • The component therapy patients received an average of 6 PRBC, 5 plasma, and 0 platelets; the whole blood group received 6.5 units (4 PRBC, 4 plasma, and 1 platelets based on the usual composition of a unit)
  • Plasma:RBC ratio was 0.8:1 for the component group and 0.94:1 in the whole blood group (statistically significant, but not clinically significant, see below)
  • The authors described a component-equivalent unit of product which is not defined. It was 12 for component therapy and 27 for whole blood.
  • There were no differences in 24-hour or 30-day mortality, and no transfusion reactions

The authors concluded that MTP using whole blood is feasible, and that it appeared to be safe and effective. They also commented that it may lead to more balanced resuscitation.

My comment: Alright, this is the last time I’ll mention study power (for a while). If a study does not have the statistical power to show a difference between groups, then seeing no difference means nothing. The absence of a difference does not mean that the two groups are equivalent. And this study of 125 patients is small potatoes for showing any difference in a crude outcome like mortality.

Besides having a small number of subjects, the average number of units given was low for an MTP. For most trauma centers, this was just over one cooler of products. Although ISS was 29, the patients don’t sound like they had huge blood replacement requirements, so it’s no wonder that mortality was the same between the two groups.

And finally, the statement about more balanced resuscitation is open to debate. The difference between 0.8 units of plasma and 0.94 units is 35cc per unit of red cells given, a little over 1 tablespoon. It’s hard to believe that this would ever make a difference clinically.

To those who read only the title or the conclusion of an abstract (or paper for that matter), beware. The devil is in the details. This study is a good start toward addressing the question posed, but needs several hundred more subjects (and a lot more blood products given) to close in on an answer.

Reference: Massive transfusion with whole blood is safe compared to component therapy. EAST Annual Assembly Quick Shot #8, 2020.

Little-Known Whole Blood Transfusion Program: Part 2

In my last post, I described a long-standing whole blood transfusion program that was implemented by Royal Caribbean Cruise Lines (RCCL)about 10 years ago. Today, I’ll dig into the specifics of their protocol and review their results.

Here is an image of the protocol. You can click it to download a full-size pdf copy.

Here are the key points in the protocol:

  • It is only implemented if it will take more than 4 hours to get the patient ashore for more advanced care
  • If the patient is hemodynamically stable, permissive hypotension to MAP 75 is encouraged and TXA infusion / Vitamin K administration are considered when appropriate. The patient disembarks at the next port of call with advanced hospital capabilities.
  • If hemodynamically unstable, two large bore IVs are maintained, TXA and Vitamin K are given when appropriate, and whole blood collection and administration are initiated. Helicopter / coast guard transport is deemed acceptable to closest advanced hospital.

And here are the guidelines for donor selection:

  • The donor hierarchy is:
    • sexual partner of the patient
    • male passenger with blood donor card
    • male passenger without blood donor card
    • female passenger with blood donor card (beware of TRALI)
    • medical staff members
    • crew
  • Only one unit is taken from each donor, and they must not be anemic

Here are the factoids describing RCCL’s seven year experience with the program:

  • 73 patients received transfusions, including 67 passengers and 6 crew
  • Mean hemoglobin on presentation was 6
  • A total of 1-6 units were given
  • Six patients ultimately died; no details were given
  • There were no ABO seroconversions, and only two adverse reactions occurred, both allergic
  • The majority of the medical staff felt that this was a valuable program

Bottom line: This is the first whole blood transfusion program I have seen outside of hospitals and the military. Royal Caribbean has incorporated lessons learned from both in developing their protocol. It includes all the principles of balanced resuscitation, including limiting crystalloids, permissive hyportension, and 1:1:1 transfusion ratios. There are many other opportunities to implement similar protocols in areas where medical capabilities are austere, and this protocol should be used as a model to develop them.