We’ve been having debates about what fluids to use in trauma and sepsis for about as long as – well – about as long as we’ve had fluids. We’ve had quite a bit of dogma going round, and a fair amount of recent dogmalysis – for example with Dan Horner heralding the end of potatoes on the ICU at St. Emlyn’s.
That’s not to mention the groundbreaking FEAST trial, of course!
In fact, most trials of fluid regimens seem to either find no difference or evidence of harm. So it’s going to be hard work for a new kid on the block to gain acceptance. This week, at St. Emlyn’s journal club, we appraised a randomised controlled trial comparing Plasma-Lyte to normal saline for patients with major trauma.
[DDET What are the theoretical advantages of Plasma-lyte?]
There’s nothing that ‘normal’ about saline, really. It’s isotonic but that’s about as good as it gets. The high chloride concentration may lead to hyperchloraemic acidosis when large volumes are infused. The pH is around 5. And there’s absolutely no potassium or magnesium to be found.
Then we have ‘Plasma-Lyte’. Wow. Sounds pretty funky? It sure is – it’s a balanced electrolyte solution with constituents that are custom designed to closely reflect those of plasma. I bet you’re itching to know what kind of extortionate price it goes for already, right? Here’s what the manufacturer says about the electrolyte composition of Plama-Lyte.
Of course, in trauma we have this concept of the ‘Triad of Death’ – hypothermia, coagulopathy and acidosis. If Plasma-Lyte might help to correct or avoid acidosis for patients with major trauma, it could potentially lead to clinical benefit.
[DDET What did these authors do? ]
The authors aimed to determine whether Plasma-Lyte or normal saline led to less acidosis in patients with major trauma. In effect, their research question was:
[In patients with severe acute injury who undergo intubation, blood transfusion, surgery or an interventional radiological procedure within 60 minutes] does [resuscitation with Plasma-Lyte or normal saline] lead to [superior correction of base deficit within 24 hours]?
Their null hypothesis was effectively:
In severely injured patients, resuscitation with Plasma-Lyte does not lead to superior correction of base deficit at 24 hours when compared to resuscitation with normal saline.
They ran a phase 2 prospective randomised, controlled trial to address this.
[DDET Did the authors ask the right question?]
In answering this question, we need to break it down. We can take each of the three parts of the research question (or 3PQ)…
The patient group
The authors included patients with severe acute injury who had penetrating injury to the neck, chest, abdomen or pelvis; GCS <9 or deteriorating by 2h after injury; systolic BP<90mmHg; injured extremity without a pulse; or need for intubation. All patients must have undergone intubation, blood transfusion, surgery or interventional radiology within 60 minutes.
Clearly, they were after the most seriously injured patients who are likely to be acidotic and to have a high mortality rate. The trial didn’t include less seriously injured patients and those who didn’t immediately go for intervention within 60 minutes. It’s therefore a slightly narrow population – but that’s perhaps not unreasonable.
What about the intervention?
The patients were randomised to receive their fluid resuscitation with either Plasma-Lyte or saline. This was blinded and the volumes infused were up to the treating clinicians. I think this is pretty reasonable.
What about the primary outcome?
The primary outcome was correction of base deficit at 24 hours. This is where we start to have problems. The most clinically relevant outcome would probably be mortality – and there are other clinical outcomes that may be important. We have to accept that the trial would have to be pretty massive to detect small differences in mortality so sometimes we do need smaller initial trials looking at surrogate outcomes to provide the justification for further work. This is one such trial – a phase 2 trial. So perhaps we can accept the fact that the most clinically relevant outcomes weren’t chosen.
What we have as a primary outcome instead is the change in base deficit at 24 hours. But is that really something that we want to know about? If we infuse a more acidic solution (saline) than Plasma-Lyte, wouldn’t we expect that Plasma-Lyte will perform better? Is that clinically relevant? This outcome just won’t tell us.
[DDET Was there any potential for bias?]
Actually, this was a quite nicely designed trial. It was prospectively registered. There was apparent allocation concealment, nice double blinding, decent randomisation, analysis by the intention to treat principle. The trial itself seems like it was pretty well designed. The baseline characteristics of the two groups were well matched.
Perhaps the only problem was attrition (or drop outs). 46 patients were included in the final analysis but the authors lost 7 patients in each group as they didn’t provide consent (although there’s not much we can do about that) and 4 patients didn’t follow the protocol sufficiently to be included in the final analysis. To be fair, if that’s our main quibble we’re doing pretty well so far.
[DDET What were the key findings?]
So, the primary outcome was the change in base deficit at 24 hours compared to the base deficit at randomisation. The Plasma-Lyte group showed a significantly greater change – by 3.1mmol/L (95% CI 0.5–5.6). There was no difference in the most clinically relevant secondary outcomes such as mortality but this study wasn’t powered to detect that. Arterial pH was higher in the Plasma-Lyte group at 24h and we can see (from their graphs) that arterial pH seemed to correct more quickly with Plasma-Lyte. As you might expect, chloride levels were higher in the saline group.
[DDET What’s the clinical relevance of this?]
That’s the key question, isn’t it? At 24h the mean base excess was -2mmol/L in the saline group and +2.1 in the Plasma-Lyte group. Both are pretty much within the normal range. (In fact you could argue that the mean was above the normal range in the Plasma-Lyte group!) Are we really convinced that this difference will make a clinical difference to our patients?
What was the overall incidence of clinically relevant hyperchloraemic acidosis in each group? We don’t know. How many patients (in terms of absolute numbers) had persistent acidosis? We can’t tell.
Lastly, we have to think about the external validity of these findings – i.e. can we generalise them to our own settings? The patients in this trial had a lot of intravenous fluid: 9 to 10 litres in each group. Is that how we practice in trauma? Perhaps not if you’re following the principles of permissive hypotension. Would that have made a difference to the findings? Quite possibly – yes.
[DDET So would you use Plasma-lyte in practice? The cynic’s perspective]
There will naturally be some cynicism out there. This trial compares 2 products manufactured by Baxter. Of course, we assume that Baxter would like it if their more expensive product (Plasma-Lyte) was beneficial. So we’d like to know a bit about the authors’ potential conflicts of interest – but we can’t find that here. There doesn’t seem to be any declaration about potential conflicts or about funding.
At the Virchester journal club when this paper was appraised, Roy Royce asked, “Is this a case of Ben Goldacre’s Bad Science?” Could the manufacturers be sowing seeds of doubt in our mind without going as far as providing clinically relevant evidence? Might those graphs showing a tendency towards earlier correction of acidosis influence us in the heat of a major trauma scenario? Will we move to Plasma-Lyte even though the evidence is not yet convincing?
[DDET A practical perspective]
We know that we can’t really answer this research question based on these data alone, unless you really think that an apparently pretty minor contribution to overall metabolic acidosis is clinically significant. The authors knew that too – they set out to run a phase 2 trial after all. So we still have equipoise based on the data. But we have 2 solutions that are commercially available, and right now we have to choose one of them for the patient we have in front of us with major trauma. What should we decide?
Maybe the issue of cost will factor. We’d expect that the funky one will be more expensive – you wouldn’t expect a fluid called ‘Plasma-Lyte’ to be cheaper than saline, right? The authors tell us about the price though. They say that saline costs $0.86 per litre while Plasma-Lyte costs $1.62. There are two ways of looking at this. Plasma-Lyte is nearly double the cost. But, on the other hand, $0.80 per litre of fluid is hardly going to break the bank for our individual patient! What’s more, according to Baxter’s Australian website, the far less funky Harmann’s + 5% Dextrose costs $8.00 for 12 litres. Plasma-Lyte costs $6.50 for the same amount.
[DDET The bottom line]
Based purely on the science and the hard facts, while the findings of this trial may justify a larger phase 3 trial, they unfortunately don’t provide the robust evidence we would need to say that Plasma-Lyte is better than saline in trauma. That’s not a criticism of this trial: it did what it was designed to do – evaluate whether Plasma-Lyte may have some kind of efficacy (not necessarily effectiveness). We now need that larger, phase 3 trial.
In the meantime, it’s perhaps more a case of ‘give less chloride, find less chloride in the blood’. And so, we’ll need to decide whether to invest an additional $0.80 per litre on Plasma-Lyte in order to avoid the potential danger of saline-induced hyperchloraemic acidosis. If you’re going to give a lot of IV fluid, this is probably something we should do. If you’re not (and I don’t in trauma), then the jury is still out.