Discussed in Oxford 16 May 14 – report by Joel Meyer
If the ICU nurse asks you to specify a target blood pressure, what do you say? Maybe a mean arterial pressure of 60 or 65… (and perhaps a bit higher in a head-injured patient).
It’s a fundamental question, with no clear answer, so where does this 65 mmHg come from?
Perhaps you could quote the surviving sepsis guidelines, which makes a strong (grade 1) recommendation for such a MAP target in septic patients. But, the guideline experts acknowledge that this ‘strong’ recommendation is based on low quality evidence (grade C), namely:
(i) it’s the target that was used in the often cited early goal directed therapy trial (in which it’s worth noting that the actual median MAPs achieved were higher: 81 +- 18 in the standard therapy and 95 +- 19 in the EGDT group).
(ii) experimentally, there is a threshold MAP for each organ below which auto-regulation fails, in other words perfusion (i.e. flow) becomes pressure dependent (perhaps 50 mmHg for the brain, 60 mmHg for the kidney… but… this is based on animal and healthy volunteer experiments and we don’t know what’s “normal” in acute illness).
Bearing in mind the shaky foundations for this often quoted and widely practised 65 mmHg target, Asfar et al investigated whether a MAP target higher than 65 mmHg might be beneficial in sepsis. In their paper they set out to compare a target of 80 to 85 mmHg against a target of 65 to 70 mmHg for a duration of 5 days in 776 septic shock patients enrolled within 6 hours in 29 centres in France. This was achieved using standard fluid and vasopressor protocols. They also postulated that a higher MAP target might have a more pronounced benefit in patients with chronic hypertension.
There was good separation between the two groups in terms of achieved MAPs, and this difference does appear from the data to be attributable to the significantly different doses of noradrenaline infused (rather than differences in fluid volumes or other catecholamines). The main finding is that there was no difference in the primary outcome, death at 28 days. This was 34% in the standard group and 36% in the high group and the two Kaplan Meier curves were identical. However in the prespecified chronic hypertension subgroup (which actually accounted for 40% of enrolled patients), there was an apparent benefit from a higher MAP target (52% versus 39% mortality). The hypertensive patients subject to the lower MAP target were also significantly more likely to require renal replacement therapy, which the higher MAP target seemed to abolish. There was a higher rate of AF in the high MAP group (26 v 11%) and a trend towards an excess of other cardiovascular adverse events.
Was it a rigorous trial? It’s strengths are that it was large, randomised, multi-centre, and real-world. The obvious limitation is the lack of blinding and placebo control, which is probably unavoidable in a pragmatic trial of physiological target ranges. The second problem is that it didn’t turn out to be trial of 65 to 70 versus 80 to 85; it was more like a trial of 72 to 77 versus 82 to 87. So it didn’t quite test the intended hypothesis (though there was a consistent 10 mmHg difference between the groups). Thirdly, the number of patients screened (4098) far exceeded the number eventually enrolled.
What can we conclude? Well, there’s no indication for a higher than ‘normal’ MAP target in sepsis. In people with chronic hypertension, perhaps a somewhat higher MAP target than ‘normal’ would be needed if renal injury is an endpoint worthy of avoiding (but this is not what the trial set out to demonstrate). The generalisability of the trial to UK sepsis practice is limited, partly because all the participating centres were in France but also because a large proportion of screened patients were excluded. Perhaps the most practically relevant finding is the consistent disparity between target and actual blood pressure achieved in critically ill patients on noradrenaline. So next time you prescribe a target MAP of 65 mmHg, it’s worth remembering that your patient might spend most of their time over 70 mmHg. And whether this is the most appropriate MAP to prescribe for your particular patient, who may or not have hypertension, remains to be discovered.