Does the 65 Trial Dial Down the Mean Arterial Pressure in Sepsis?

May 24, 2020

“This whole thing is not about heroism. It's about decency. It may seem a ridiculous idea, but the only way to fight the plague is with decency.”

-Albert Camus

Background

In 2013, Dünser and colleagues communicated a rogue viewpoint in shock resuscitation – let us do away with strict macro-hemodynamic goals in favour of tissue perfusion end-points. They suggested ‘context sensitive’ mean arterial pressure [MAP] targets as low as 45 to 50 mmHg; that is, a mean pressure low enough to provide ‘heart and brain’ perfusion so long as tissues are well fed. They termed this ‘permissive hypotension’ to harken permissive hypercapnia in acute respiratory distress syndrome [ARDS]. Remember when large tidal volumes were used to normalize PaCO2 in ARDS? You might not, but that was previously a goal; and the result? Tremendous pulmonary trauma – a time when prophylactic chest tubes were suggested in ARDS because of the high incidence of lung fracture. Yes, chest tube insertion in preparation for the pulmonary trauma caused by the heavy-handed tidal volumes dialed in for the gratification of a 40 mmHg PaCO2. Smugness swells boundless and supreme with the retrospectoscope pressed firmly into our orbits.

What if what we’re doing for mean arterial pressure also follows a normalization fallacy? Vasoactive infusions are not benign; will clinicians battling the next pandemic in 2040 calmly maintain erstwhile frighteningly low mean arterial blood pressure in shock? Will they view 2020 shock resuscitation disparagingly?

The excellent 65 Trial, like ANDROMEDA-SHOCK last year, continues a conversation that challenges our basic assumptions on physiology, cause-and-effect and underscores our predilection for tangible bias.

What They Did

The 65 Trial was a pragmatic, multi-centre, randomised controlled trial. Patients over the age of 65 were recruited from 65 National Health Service [NHS] adult, general, critical care units. They were with vasodilatory hypotension and having had received vasopressors for at least one hour.

Those randomized to the intervention group received ‘permissive hypotension’ [i.e. mean arterial pressure target range of 60 – 65 mmHg on vasopressors]. Those in the control group received usual care; many different vasoactives were employed.

The primary outcome was 90-day mortality while secondary outcomes were: mortality at hospital discharge, duration of survival to longest available follow-up, duration of advanced respiratory and renal support, days alive and free of advanced respiratory support and renal support, duration of critical care unit and acute hospital stay. They also assessed long-term cognitive function.

What They Found

2600 patients were randomized and 2463 were in the final analysis; the patients were similar at baseline. Mortality in the permissive hypotension group was 41% while it was 43.8 % in the control group; this was not statistically significant. With respect to secondary outcomes, there was a reduction in total vasopressor dose, and no difference in duration of mechanical ventilation or cognitive function.

Thoughts

It is known that when blood pressure is maintained within the limits set by brain and renal auto-regulation, there is a poor correlation between blood pressure and micro-circulatory flow. Similarly, when norepinephrine raises mean arterial pressure, flow within the micro-circulation is capricious at best. On the other hand, vasodilatory hypotension may augment microcirculatory flow.

Why do the aforementioned results confuse us? The answer may lie with the over-emphasis of blood pressure and under-emphasis of basic physiology in sepsis guidelines. Measuring blood pressure is a form of ‘tangible bias,’ which taps into our predilection for normalization fallacy. Blood pressure is relatively easy to measure and what we measure is afforded undue importance. In addition, when we measure a variable and find it abnormal, especially in a sick human, it is too tempting not to correct.

How do we reconcile the disparity between macro-hemodynamic blood pressure and micro-circulatory flow? As previously discussed, blood pressure is a determinant, but not necessarily an indicator of peripheral perfusion; because all perfusion is local! Tissue perfusion depends upon central arterial pressure – as reflected in the MAP – and local conductance [i.e. the inverse of resistance]. If every tissue bed in the body increased its conductance [i.e. decreased its resistance] in exact proportion, then mean arterial blood pressure would fall, yet whole body tissue perfusion would be unchanged. Thus, the danger posed by vasodilatory hypotension is when one, or some, tissue beds increase their conductance out-of-proportion to others. In other words, if tissue conductance rises with disparity in the body, then central arterial pressure will fall and the tissue beds with increased conductance will sustain flow. However, the tissues with unchanged [or increased] conductance suffer.

And the converse also holds. If the conductance of every tissue bed were to fall in exact proportion, then MAP would jump, yet whole body tissue perfusion would be unchanged. Thus, the problem is when some tissue beds drop their conductance relative to others and especially if conductance falls to zero. Zero conductance is observed when the critical closing pressure for the insulted vascular bed is greater than the mean arterial pressure – all downstream tissues are flow-starved – though mean arterial pressure may rise. An extreme example of this is resuscitative endovascular balloon occlusion of the aorta [REBOA] – the conductance distal to the inflated balloon is zero; a less extreme example is the provision of intravenous alpha agonists.

So, the results of the 65 Trial are not entirely surprising. Targeting a lower mean arterial pressure does not necessarily deprive tissues of perfusion and may actually improve flow if critical closing pressures fall below mean arterial pressure. The trouble is that each organ has its own conductance curve and the slope of each organ’s curve adapts differently to an equally dynamic physiological milieu within and between patients. A patient with a 90% left main stenosis has a very low, and fixed, cardiac conductance; therefore, vasodilation of other tissue beds poses an existential risk. Whereas an 18-year old with pneumococcal bacteremia and anaphylaxis from amoxicillin will have high total body tissue conductance, a low mean arterial pressure and, potentially, preserved organ perfusion. To the credit of the 65 Trial, enrolling those at least 65 years of age is anticipated to concentrate the former, rather than the latter patient, yet mortality was lower in the permissive hypotension group [absolute risk difference, −2.85%; 95% CI, −6.75 to 1.05; P = .15] and these patients received fewer vasoactive medications.

Conclusion

In totality, I wonder if we are observing the ‘heroism’ of early goal directed therapy slowly transmute into resuscitation ‘decency’? This approach, marked by restricting both intravenous fluids and vasoactives offers time and antibiotics the ultimate agency. If, instead, we turn our lonely eyes to Albert Camus and The Plague, Dr. Rieux claims not to know what ‘decency’ is; though, in general, he thinks it consists simply in doing his job. In decency, I hear twangs of Levinas’ non-intentionality, or being that cannot impose mastery upon the world, the element of self that does not formulate knowledge in the classical sense. In other words, decency as an expression of time:

“Duration as pure duration, non-intervention as being without insistence, as being that dare not speak its name, being that dare not be; the agency of the instant without the insistence of the ego which is already a lapse in time, which is ‘over before it’s begun!’”

With this reading and in this distemperate moment, I am assured that countering the plague is, indeed, not rooted in heroism, but decency.

Best,

Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org