Today is another landmark in the history of sepsis research. The long awaited results of the ProMISe trial are finally published in the New England Journal of Medicine. At 56 hospitals across the United Kingdom we’ve been working tirelessly to recruit patients to this awesome, cutting edge randomised controlled trial comparing early goal directed therapy to standard care for patients with severe sepsis.
This last year has been amazing for research into early goal directed therapy. We’ve been lucky enough to have two huge randomised controlled trials published from Australasia and the United States. The ARISE and ProCESS trials both found no difference in 90-day/60-day mortality between patients who were randomised to receive early goal directed therapy and those who received standard care. But would things be different in the United Kingdom? Could there be a small treatment effect that was not detected in the previous two randomised controlled trials? Despite their large sample sizes the 95% confidence intervals from those trials could not exclude the possibility of a 20% relative risk reduction for 90 day mortality. If there really is a treatment effect of that magnitude then early goal directed therapy could still be useful.
Who was included in the ProMISe study?
Essentially we had patients with septic shock. All patients had to have two SIRS criteria, a known or suspected infection and either hypotension (systolic BP less than 90 after a litre of fluids) or a lactate of at least 4 mmol per litre. After consent (or assent from a relative or independent representative), the patients were randomised to receive either standard care (in which case the clinicians could do whatever they felt best) or early goal directed therapy (which involved following the algorithm below). Because of the nature of the intervention, all patients in the intervention group ought to have had a central line and an arterial line inserted, and should have undergone 6 hours of continuous ScVO2 monitoring.
All of the patients in this trial were then followed up for the primary outcome of all-cause mortality after 90 days. They looked at other outcomes too, such as organ dysfunction, length of stay and they ran an economic analysis. Ultimately, this was a large trial: 1,251 patients took part, which gave the study enough power to detect a 20% relative reduction in mortality assuming that the 90-day mortality would be (a whopping) 40%.
What were the key findings of this study?
The bottom line is that there was no difference in 90-day mortality, so the findings of this trial don’t support the protocolised care used in this trial. In total, 29.5% of patients in the EGDT group and 29.2% in the control group died. The 95% confidence intervals were fairly tight too. The relative risk was 1.01 with confidence intervals from 0.85 to 1.20.
The secondary outcomes tell a similar picture: costs were similar, length of hospital stay was similar. Patients in the EGDT group had significantly higher SOFA scores at 6 hours, received more cardiovascular support and had longer stays in the ICU than patients in the control group.
So, for sure, we can conclude that ProMIse showed no difference between EGDT and standard care, which was also the finding in the ARISE and ProCESS trials.
But were there any methodological problems with this trial?
This is a large, well conducted randomised controlled trial at 56 centres. The groups were well matched at baseline, data were analysed by the intention to treat principle and there was a very good follow up rate for the primary outcome. In general, the trial holds up to scrutiny and deserves to be published in the NEJM as it’s definitely a landmark trial. It definitively shows that rigidly following that protocol in patients who meet the criteria for septic shock isn’t beneficial compared to what we’re doing right now. There are still a few questions we might ask, though…
Is this really EGDT RIP?
Possibly. And possibly not. In this study 92.1% of patients in the intervention group had a central line inserted within 6h. But, in the control group, 50.9% of patients also had a central line inserted – and the time to insertion was similar in both groups. In the intervention group 74.2% of patients had an arterial line inserted, but so did 62.2% in the control group – and again the timing was similar. Both groups received fluids in the first 6h (1.75L in the intervention group, 1.5L in the control group), both groups received vasopressors (53.3% versus 46.6%). Both groups were admitted to ICU (88.2% versus 74.6%). More patients in the intervention group received dobutamine and packed red cells but numbers were small, so if those interventions really are the beneficial ones then this study is probably underpowered to detect differences in that subgroup.
Perhaps what we’re seeing is contamination, where patients in the control group are actually exposed to the intervention being studied – or at least parts of it. Because EGDT is so ingrained in us and because our main focus is to treat patients, maybe the sickest patients in the control group were still receiving EGDT. And maybe clinicians selectively using EGDT in the sickest patients from the control group is what made this a negative trial.
What’s more, the inclusion criteria seem to incorporate a fairly broad group of patients. We have the hypotensive patients, who I think we would all agree have septic shock. But we also have the normotensive patients with a high lactate – which could be as little as 4.1 mmmol/L. If those patients cleared that lactate within an hour, returned to normal physiology and received early antibiotics (which all patients did) would we really want to insert central lines, arterial lines and continuously monitor ScvO2 for 6 hours? I’m not so sure that we would in our current practice.
To my mind, this trial justifies our current approach. If your septic patient is sick, go for the EGDT approach. Insert a central line, insert an arterial line, fill the patient up, give vasopressors if they’re still hypoperfused. That’s what happened in this trial – it doesn’t knock that approach. It they’re not so sick, then don’t.
Maybe that’s all this trial is really telling us. And maybe that’s a limitation of the RCT to answer these questions.
Where next for sepsis care?
With three huge RCTs just published, we’re now waiting to see what will happen when the data are combined and subgroups can be analysed with more statistical power. Is there any effect of EGDT in the hypotensive subgroups? Are there any groups that might benefit? Are there any particular elements of the pathway that seem to produce an effect?
ProMISe hasn’t killed EGDT. Not yet. There are still a good few questions to answer.