JC: The RePHILL trial. St Emlyn’s

Estimated reading time: 13 minutes

This week we see the publication of the RePHILL trial. This is something we have been looking forward to for some time. A randomised controlled trial of the use of packed red cells, LyoPLAS and saline in the treatment of hypovolemic shock in the prehospital environment. The paper is published in Lancet Haematology and the paper itself was presented live on the critical care reviews website which you can watch on the link below. I was lucky enough to be invited to do the editorial for the presentation on which this blog is based. If you have the time to watch the full presentation I would recommend you do so as there is some really interesting information and rationale presented by the authors that is not obviously apparent from the paper.

https://criticalcarereviews.com/livestreams/rephill

You should also read the full paper which is now available as an open access publication on the Lancet Haematology website. The abstract is below, but as we always say at St Emlyn’s, please read the full paper yourself and come to your own conclusions. Judging from the twitter storm that followed publication this is very important with this paper. It would appear that many just read the abstract and came to somewhat erroneous conclusions (as evidenced by getting the data wrong). Anyway, we are confident that the St Emlyn’s readership would not fall into that trap.

Background

What at first seems obvious is not always the case. This is both the beauty of research and also its greatest frustration. As many regular readers will know, here at St Emlyn’s we love research that advances science and which demonstrates to us that what we are doing is the right thing and in particular that our interventions make a difference.

For those of us in my generation we have seen substantial changes to the approach of fluid resuscitation over the last 20-30 years. My initial experience of dealing with the hypovolaemic trauma patient was to witness large volumes of crystalloid being used to pursue what we believed to be a ‘normal’ blood pressure. The logic at the time appeared to be sound; the body could cope with haemodilution but not with hypovolaemia and so taking a patient with an Hb of 140 to one of 100 whilst maintaining an adequate circulating volume made sense and could easily be argued in pathophysoplogical terms and also in anecdote. I saw many patients survive with this regime, some from what appeared to be significant hypovolaemic/shocked states. Not only did it make sense, but it made pathophysiological sense, but we now know it was wrong.

A few years later we started to see the use of colloids increase and the ‘cool kids’ moved over to the use of gelofusine/haemaccel as the resuscitation fluid of choice. Not only did it achieve the required volume expansion but it also stayed in the circulation longer and supported renal function (or so we thought at the time). I personally regularly argued that it was the resuscitation fluid of choice.

When we look back now to what is really not that long ago such strategies seem misguided, bizarre and in many cases downright dangerous. How could we have been so naïve and stupid to think that using basic pathophysiological logic would naturally lead to better outcomes for our hypovolaemic trauma patients? The cool kids were no longer cool as the new kids on the block followed new regimens that clearly made al the difference.

That brings is to the current day when the clear pathophysiologic argument that blood is what we lose in trauma and therefore blood is what we must replace makes perfect sense. Pasta water is bad, blood is good and this is now resuscitation dogma.

The logic of such a statement is of course obvious and I can see why this has promulgated our thinking over many years but take a step back and think this through a little closer.

What are we really putting into our patients?

A bag of blood isn’t a bag of blood. In the UK at least it is a bag of packed red cells which has has the platelets, plasma and calcium removed from it. From trials such as PROPPR, PAMPER and others we are increasingly aware of the likely benefits of replacing the other components of blood through the addition of bags of platelets and plasma with the aim of achieving a 1:1:1 ratio of products as part of major transfusion plans together with the use of TXA and calcium (although observational data suggests that we don’t achieve that 1:1:1 ratio very quickly in practice).

A bag of packed cells has a biochemical and metabolic profile that should scare the pants off anyone who has ever bothered to find it out. The table below shows the findings of a European study that looked at blood with an average shelf life of 6 days (much shorter than many blood supplies available in the UK).

As you can see the components are not very physiological with particular concerns regarding the potassium levels, pH and calcium (together with chelating agents). If PRBCs came in a clear plastic bag and were kept on a shelf we would be very reluctant to use them in the volume and speed that we do when using PRBCs in trauma.

At this point it’s perhaps worth reflecting on Karim Brohi’s recent thoughts on the the evolving triad of doom in trauma. You will of course remember that the original triad was hypothermia, acidosis and coagulopathy. In recent years, as we have become mode adept at managing all aspects of trauma he (and others) have modified this to coagulopathy, hyperkalaemia and hypocalcaemia. All of which may be profoundly influenced by transfusion policies and the biochemical/metabolic profiles of the products we give.

Plasma replacement therapy similarly has its challenges as a resuscitation fluid. It may again be a cause of hypocalcaemia in our trauma patients which has been shown in trials like PAMPER and COMBAT to be strongly associated with adverse outcomes.

The point here is that when we think of replacing blood lost in trauma we are actually substituting it with products that are physiologically highly abnormal and potentially fatal. Not to mention the well established concerns around transfusion reactions and more that are concerns in any blood transfusion. We should always be sceptical in our practice and therefore the logical argument that blood lost must be replaced with prbcs is open to challenge and research.

The RePHILL trial attempts to answer this question and I believe that as clinical scientists we must support and applaud their efforts in doing so. The trial has not been without scepticism amongst the resuscitation community, more on that later, but the important point is that the question is being asked, and that’s science. It is only through research, experiment, debate and further study that we will hope to build a picture of the role of blood products in the management of trauma.

Is this study likely to be definitive? It’s unlikely that it ever could. Trauma is a diverse disease across different pathologies, health economies and systems and so no study of this type and size will answer all questions for all parties, but every study provides data to build the evidence base that underpins our practice.

The study

Please read the study, and at least consider the abstract above. The authors deserve great praise in asking this question at the beginning and for their persistence in the delivery of this intervention in an extremely challenging environment with very complex patients. This trial now sits with other UK based studies in pre-hospital care such as AIRWAYS-2 that demonstrate and established an enviable expertise in this area of randomised controlled trials in prehospital care.

It’s unfortunate that it was stopped early, but that has been the case with a larger number of trials in recent years and the approach to determine a safe stopping point on the basis of the DMC and a Bayesian analysis is entirely appropriate under the circumstances.

Outcomes

Much has been made about the composite outcomes in this trial. The combination of death and lactate clearance is unusual. In general, I am not a fan of composite outcomes and in particular those that mix hard patient orientated outcomes (POOs – such as death) with Monitor (MOOs) or Laboratory (LOOs) orientated outcomes. It may be a necessity to use composite outcomes in some conditions such as chest pain where death, MI or revascularisation is a common combo as these are all clearly related and to a degree independent. However, in RePHILL we have a more challenging combination of death (POO) together with lactate clearance (LOO). These are not obviously additive to create a wider picture of outcomes and in many individual cases one can imagine that they may well move in opposite directions with patients clearing lactate and subsequently dying and vice versa.

In fact, we have seen that the authors were somewhat fortunate in that the composite outcome, and the secondary analyses all demonstrated the same lack of effect. It would have been a far more challenging, and perhaps interesting, commentary had they pointed in different directions and I’m intrigued as to whether the authors considered this.

A negative (non-positive) result

The result has presented a challenge to many who work in prehospital care who were clearly surprised at the lack of impact of the use of blood. The results fail to show a difference in statistical terms, and also in clinical terms. This appears to be a very neutral outcome for the two interventions (some would say it’s a negative trial, but that kind of misses the point of research). The Bayesian analysis demonstrates that it is highly unlikely that there is a substantial difference in outcomes between these interventions, in this group of patients, within these healthcare systems and we need to consider how all of these factors come together to perhaps influence the magnitude of effect here.

Patients may be a factor here. Other studies in alternative health economies such as wartime, or where penetrating trauma is more prevalent, where injury to intervention times differ or where less clear fluid has been administered to their arrival  may see and experience different outcomes to the ones here.

The authors have drawn attention to a potential difference in survival at 3 hours post intervention but I think we should be very cautious about attributing too much value on a sub group analysis, that does not meet statistical significance and which is not sustained at later time points. However, an earlier increase in survival may give the impression to HEMS crews that the intervention works within the time frame that they are with the patient.

There are several other analyses that are extremely interesting. One that caught my eye was in the supplementary data and is the proportion of patients in both groups who have clinically significant low Hb’s on arrival in the emergency department. Surprisingly, there was very little difference between the two groups. This implies that the impact of giving early blood is not in increasing the delivery of oxygen (especially because PRBCs have low levels of 2,3 DPG and therefore do not release O2 very well). There is a small shift to the left for patients treated with saline, but relatively few who really drop their Hb.

This, and other considerations, have led to clinicians comment on the use of plasma first in the resuscitation of patients and I can see the logic of this, and also in the results of trials such as PAMPER. It is certainly an area deserving of more research and consideration.

Plasma first resuscitation as a strategy is fascinating as there are obvious impacts in clotting, but also in the potential impact on the glycocalyx and endothelial performance. I suspect we will see more research in this area in the next few years.

One common theme of those reviewing the paper is whether there were enough patients in the study who had the potential to benefit. This is the goldilocks concept that within the cohort there are three groups of patients. Those that will never benefit because death is inevitable, those that never benefit because not sick enough to benefit and those in the middle where the intervention may truly make a difference. The impact of this is that the trial becomes effectively underpowered to demonstrate a difference (remembering that the sample size calculation in this trial was already highly ambitious in my opinion). This is a valid consideration and a problem with a lot of emergency trials, but it also reflects reality with clinicians in the study making the decision to randomise at an appropriate time. It is possible that there are subgroups of patients who are more likely to benefit from prehospital transfusion, but there is little signal to this in the data. If there are, then perhaps these are likely to be those who are actively bleeding, and in my opinion and experience notably those with certain patterns of penetrating trauma. That view is conjecture though and we would benefit from more data to support or refute such thinking.

Will it change practice?

Possibly. For those who are yet to embark on the blood journey there may now be a significant argument that the bureaucracy and effort required to start using blood products may not be worth it. Others who are already using blood products are likely to continue using them. One comment I heard from a colleague was that they would continue to use PRBCs prehospitally as that’s what we use in hospital and it makes sense to do the same. There is some logic in this as many if not all of these patients will require subsequent blood transfusion during their hospital stay.

Where next?

RePHILL is a great trial in many respects, and one that has demonstrated not just important results, but evidence of the practicalities of running such trials successfully in the UK. I love trials that cast doubt on current belief systems and this trials does that. Whether there are specific groups of patients who may benefit from prehospital transfusion remains to be seen, and if there are then the question of how to identify them similarly so. Similarly, there are alternative products and strategies for prehospital transfusion that have shown different results in other health economies and potentially in future trials. Bringing all that information into a coherent strategy is a challenge for prehospital care systems.

New work is underway and I am delighted to see that the SwiFT trial of whole blood use in the management of traumatic hypovolaemia is in the set up phase across the UK. Similar studies are planned in the US and in the next decade we hope to see more. Of interest the use of whole blood has already started in some UK air ambulances. The evidence base for it is arguably not yet there, but this is one area of practice, often outside of the NHS, where practice change often runs ahead of a robust evidence base. Whether that is excellence in innovation or a leap of faith remains to be seen,

vb

S

@EMManchester

References and further reading

Critical Care Reviews LiveStream. https://criticalcarereviews.com/livestreams/rephill

The RePHILL trial https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(22)00040-0/fulltext

Simon Carley, “JC: The metabolic and biochemical characteristics of packed red cell transfusions.,” in St.Emlyn’s, August 23, 2019, https://www.stemlynsblog.org/jc-the-metabolic-and-biochemical-characteristics-of-packed-red-cell-transfusions/.

Zaf Qasim, “Everything old is new again – whole blood in the trauma bay – St Emlyn’s,” in St.Emlyn’s, November 9, 2018, https://www.stemlynsblog.org/whole-blood-in-trauma-st-emlyns/.

SwiFT trial https://www.bartshealth.nhs.uk/news/landmark-uk-study-launches-to-save-hundreds-more-lives-4592

Iain Beardsell, “Hypocalcaemia, Trauma and Major Transfusion. St Emlyn’s,” in St.Emlyn’s, May 22, 2021, https://www.stemlynsblog.org/hypocalcaemia-trauma-and-major-transfusion-st-emlyns/.

Janos Baombe, “JC: Does earlier TXA save lives? St.Emlyn’s,” in St.Emlyn’s, November 12, 2017, https://www.stemlynsblog.org/earlier-txa-saves-lives-review-st-emlyns/.

Thanks so much for following. Viva la #FOAMed

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