The 65 trial compares MAP targets of >65 mm to >60 mm in treating vasodilatory hypotension. This trial challenges decades of protocols which have targeted a MAP >65 mm. As such, it is a courageous and practice-changing study. However, we need to be realistic about the study’s limitations.
This multi-center RCT was implemented in 65 ICUs in the United Kingdom.1 It involved 2,455 patients over 65 years old being treated with vasopressors for management vasodilatory hypotension. Patient groups were very well-matched at baseline (table below). Enrollment occurred in the ICU, within <6 hours of vasopressor initiation.
Patients were randomized to target permissive hypotension (MAP goal 60-65 mm) versus usual care. Targeting a MAP of 60-65 mm resulted in the use of lower doses of vasopressors:
On average, patients in the permissive hypotension group achieved the target MAP of 60-65 mm about half the time:
The MAP was on average 6 mm lower in the permissive hypotension group. This is roughly what one might expect (targeting a MAP >60 mm vs. a conventional MAP >65 mm).
Permissive hypotension allowed for more rapid weaning off vasopressors. The median duration of vasopressor use was 33 hours with permissive hypotension vs. 38 hours with conventional therapy (figure below).
Fluid utilization was identical across both groups of patients:
The primary endpoint was mortality. 90-day mortality was 2.9% lower in the permissive hypotension group (CI -6.7% to +1%, p=0.15). An adjusted analysis using multilevel logistic regression with unit-level random effects detected a borderline significant mortality benefit (table below).
The mortality difference between the two groups took a rather long time to diverge (survival curves below). Mortality differences weren’t close to statistical significance at the time of hospital discharge (p=0.3) – it was only after hospital discharge that potentially significant differences emerged.
The subgroup analyses were surprising. Permissive hypotension seemed to be the most beneficial among patients with chronic hypertension and those with septic shock (groups that might be expected to be at the greatest risk of harm from permissive hypotension). Given the multiple statistical comparisons, it’s hard to know whether these differences represent signal or noise.
Secondary endpoints showed no differences in renal function, ICU length of stay, ventilation, or 90-day cognitive outcomes:
some opinions on the study
#1. What is my pre-trial expectation that different MAP targets affect mortality in patients >65 years old?
Very low. It's extremely difficult to ever show mortality benefit in a critical care trial, so our default expectations should be low. Furthermore, previous studies (SEPSISPAM and OVATION) have found no mortality effect from different MAP targets.2,3
Lamontagne et al. performed a patient-level meta-analysis which combined data from SEPSISPAM and OVATION.4 This study evaluated the interaction of MAP target and age. They found a non-significant trend towards increased mortality with higher MAP targets in older patients (figure below). However, their conclusion was that this was not a statistically significant finding (in the graph below, the 95% confidence interval mapped out in grey never increases above one):
If prior trials found no mortality difference and there is no strong interaction with age, then we should not expect to find any mortality difference in this study.
#2. Does the 65 Trial support the concept that vasopressor exposure is more dangerous in older patients?
Not really. Subgroup analysis in this trial doesn't show any robust interaction between age and the effect of permissive hypotension (below). This undercuts the study’s initial premise. Overall, this data is consistent with a lack of any strong relationship between age and side-effects from higher MAP targets (consistent with prior data discussed in #1).
#3. What is the meaning of the mortality trend?
There is a non-significant (p = 0.15) trend towards reduced mortality in patients treated with permissive hypotension. There are several reasons to doubt that this represents a true mortality benefit:
- A pre-study probability for mortality benefit is low, as explored above:
- Prior studies haven’t found a mortality benefit.
- There is no persuasive evidence that patients over 65 years old behave differently from younger patients (so there is no reason to expect the 65 trial results to differ from previous trials).
- Mortality rates diverge late – largely after discharge from the hospital.
- There are no signals of benefit in intermediary endpoints (e.g. renal function, respiratory function, ICU length of stay, fluid balance). As such, it’s unclear why a lower vasopressor dose should reduce mortality.
- The amount of separation in blood pressures between groups was small (~6 mm), with considerable overlap. It’s extremely difficult to believe that this small degree of separation could cause a change in all-cause mortality. For comparison, the SEPSISPAM trial found no mortality difference despite considerably greater separation in blood pressure (figure below).
A complex, adjusted analysis did find a barely significant improvement in mortality. It’s dubious why an adjusted analysis should be required in such a large MC-RCT (randomization should account for baseline differences – and based on the table above the groups were well-matched at baseline). Adjusted analyses are unusual for large MC-RCTs with patient-level randomization. Furthermore, they don’t have a great track record. The only other critical care trial I’m aware of that used adjusted analysis for a patient-randomized MC-RCT was the ACURASYS trial.5 That study used an adjusted mortality benefit to scrape its way to a mortality benefit from cisatracurium in ARDS – a conclusion which was later disproven by the ROSE trial.6
#4. Will meta-analysis with prior studies help sort this out?
Probably not. I performed a meta-analysis combining the 65 Trial, SEPSISPAM, and OVATION below (using RevMan5.3). Combining the studies doesn’t change anything (the p-value is 0.14, which doesn’t budge at all):
A patient-level meta-analysis which looks only at patients over 65 would yield more optimistic results, with a lower p-value. However, as discussed in #2, it’s debatable whether this subgrouping of available data is justified. Furthermore, a meta-analysis including only patients over 65 years old will likely be strongly dominated by the 65 Trial, so it will predominantly be just a reflection of the 65 trial itself (i.e. the 65 trial will probably contribute >80% of the weight in the meta-analysis). So meta-analysis is unlikely to clarify the mortality question.
#5. Should this trial change practice?
I think it should. The study shows that targeting a MAP >60 mm is safe. With a philosophy of less-is-more, there may be a default preference towards using lower doses of vasopressors and discontinuing them earlier. Regardless of whether the mortality trend is real, it supports the safety of targeting a MAP >60.
Systemic Perfusion Pressure = MAP – CVP
High CVP –> Need a higher MAP to achieve adequate systemic perfusion pressure
Low CVP –> Can achieve adequate systemic perfusion pressure with lower MAP
Perhaps more important than the MAP value is the systemic perfusion pressure, which is the driving pressure directing flow across most organs. Historically, large volumes of fluid were used to push up the CVP >12 mm. In the context of a high CVP, a high MAP may be required to achieve an adequate systemic perfusion pressure. Currently, the pendulum is swinging towards more conservative use of fluid. It’s possible that if we maintain patients at a lower CVP, then patients won’t require a high MAP to achieve adequate perfusion.
Targeting a MAP >60 mm seems like a sensible initial option for many patients. However, hemodynamic management requires individualization, with close attention to how any specific patient responds. There is no single optimal MAP for every critically ill patient. This heterogeneity is one reason that the 65 Trial may have faced an impossible task of demonstrating mortality benefit.
#6. What limitations should we bear in mind?
Several caveats are notable:
- The 65 Trial excluded patients below 65 years old. The study suggests, by extrapolation, that a MAP target >60 should be adequate in younger patients (who often have a lower blood pressure at baseline). However, this has yet to be proven. If there is an interaction with age, then lower MAP targets could be dangerous in younger patients.
- Treatment in the 65 Trial began some hours into the patient’s ICU stay. Therefore, it’s unclear whether a MAP target >60 mm would be adequate during the initial phase of resuscitation (which may often occur in the emergency department).
- All patients in the 65 Trial were in the ICU. Therefore, this study cannot necessarily be used as direct evidence that patients with a MAP >60 mm don’t require admission to an ICU.
- Although patients in the “permissive hypotension” group were targeted to a MAP of 60-65 mm, their blood pressures were very often 65-75 mm. Thus, it’s debatable whether this was truly “permissive hypotension” or merely accurate achievement of a conventional target of 65-75 mm. It’s possible that the target of 65-75 mm is optimal, but usual care was routinely overshooting the mark.
- The trial compared two unblinded interventions which required different intensities of nursing care (it's harder to achieve a MAP of 60-65 mm than usual care). This may bias outcomes in favor of the more labor-intensive intervention, which causes the patient to receive more nursing attention.
- Targeting a MAP >60 mm in real-world clinical practice (beyond the tightly regulated context of an RCT) might expose patients to longer durations with a MAP in the 50s – which might not be safe.
- The 65 trial randomized ICU patients over 65 years old with vasodilatory shock admitted to ICU to target a MAP of 60-65 versus conventional therapy.
- Patients in the 60-65 mm arm on average had MAPs ~6 mm below the conventional arm. Fluid utilization was not different between the two groups.
- Targeting lower MAPs didn’t have a statistically significant effect on mortality, renal function, respiratory function, ICU length of stay, or 90-day cognitive outcomes. Targeting a lower MAP accelerated liberation from vasopressors by an average of 5 hours.
- This study demonstrates that targeting a MAP >60 mm in ICU patients over age 65 is safe and potentially beneficial within the context of an RCT. However, as with any hemodynamic intervention, careful monitoring is likely important to ensure that patients are responding favorably.
- 65 Trial Manuscript and editorial (JAMA)
- 65 Trial (Celia Bradford, TheBottomLine blog)
- The 65 Trial (Simon Carley, St. Emlyns Blog)
- 65 Trial presentation at Critical Care Reviews 👇
- 1.Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension. JAMA. February 2020. doi:10.1001/jama.2020.0930
- 2.Asfar P, Meziani F, Hamel J, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173
- 3.Lamontagne F, Meade M, Hébert P, et al. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42(4):542-550. doi:10.1007/s00134-016-4237-3
- 4.Lamontagne F, Day A, Meade M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med. 2018;44(1):12-21. doi:10.1007/s00134-017-5016-5
- 5.Papazian L, Forel J, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. doi:10.1056/NEJMoa1005372
- 6.National Heart, Lung, and Blood Institute PETAL Clinical Trials Network., Moss M, Huang D, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. doi:10.1056/NEJMoa1901686