65 Trial - Targeting Lower MAPs in Vasodilatory Shock in Older Patients

Vasopressors are used to restore perfusion in vasodilatory shock, but their use isn’t benign — especially in older patients with limited physiologic reserve. Prior meta-analyses hinted that higher MAP targets might increase mortality in older patients, possibly due to increased vasopressor burden. The 65 Trial was the first large-scale RCT powered to test whether permissive hypotension (MAP 60–65 mmHg) could reduce mortality compared to usual care in ICU patients aged ≥65 years with vasodilatory shock.

Design

• Design: Multicenter, pragmatic, randomized trial across 65 ICUs in the UK
• Population: 2600 ICU patients ≥65 years old with vasodilatory hypotension on vasopressors
• Intervention:
• Permissive Hypotension: MAP target 60–65 mmHg
• Usual Care: MAP at clinician discretion
• Primary Outcome: 90-day all-cause mortality
• Secondary Outcomes: ICU and hospital mortality, organ support duration, cognitive and quality-of-life measures

Key Findings

• 90-day mortality:
• Permissive group: 41.0% (66.7 mm Hg mean MAP)
• Usual care: 43.8% (72.6 mm Hg mean MAP
• Absolute risk difference: –2.85% (95% CI: –6.75 to +1.05), not statistically significant (p=0.15)
• Adjusted OR: 0.82 (95% CI: 0.68–0.98) → suggests potential benefit, but cautious interpretation warranted
• Vasopressor exposure:
• Lower in permissive group (median duration 33h vs 38h; lower cumulative doses)
• Serious adverse events: Similar between groups
• Chronic HTN subgroup: Mortality benefit more pronounced (38.2% vs 44.3%, adjusted OR 0.67, interaction p=0.047)

Authors’ Conclusion

Permissive hypotension (MAP 60–65 mmHg) did not significantly reduce 90-day mortality, but the results suggest a possible benefit, especially in patients with chronic hypertension. These findings should be interpreted in the context of the confidence intervals and the exploratory nature of subgroup results.

RAMMBO (First10EM)

Strengths

• Largest RCT of MAP targets in older ICU patients
• Pragmatic design with real-world generalizability
• Excellent protocol adherence and data completeness
• Subgroup analysis for chronic HTN pre-specified

❌ Limitations

• Open-label design
• Primary outcome narrowly missed statistical significance
• Subgroup effects (e.g., chronic HTN) require confirmation
• Potential for performance bias in co-interventions

The 65 Trial didn’t show a statistically significant reduction in 90-day mortality with a MAP target of 60–65 mmHg in older ICU patients, but the findings suggest this strategy is safe and potentially beneficial.

However, there are important caveats. Although the target in the permissive hypotension group was 60–65 mmHg, the mean MAP actually achieved was 66.7 mmHg, slightly above protocol. This reflects a real-world challenge: clinicians may be reluctant to let MAP fall below 65, especially in critically ill older adults. The relatively narrow MAP separation (66.7 vs 72.6 mmHg) may have blunted the trial’s ability to detect a true difference in outcomes, particularly for subgroups where more aggressive reduction might have a larger impact.

Still, this large, pragmatic RCT reinforces a key message: we don’t need to reflexively chase MAPs >70–75 mmHg in older patients. A strategy of permissive hypotension appears safe, feasible, and possibly beneficial — but further trials with tighter MAP adherence or larger separations are needed to confirm the mortality signal and better guide individualized care.