JAMA FEBRUARY 12, 2020

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial (65 Trial)

Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, Sadique MZ, Grieve RD, et al; 65 Trial Investigators

Bottom Line

In older critically ill patients with vasodilatory hypotension, a permissive hypotension strategy targeting a mean arterial pressure of 60-65 mmHg did not significantly reduce 90-day mortality compared to usual care, though it did successfully reduce overall vasopressor exposure.

Key Findings

1. The primary outcome of 90-day all-cause mortality was 41.0% in the permissive hypotension group compared to 43.8% in the usual care group (absolute difference, -2.85%; 95% CI, -6.75% to 1.05%; P=0.15).

2. The permissive hypotension strategy resulted in significantly reduced vasopressor exposure, with a median duration of vasopressor therapy of 33 hours compared to 38 hours in the usual care group.

3. The total norepinephrine-equivalent dose of vasopressors was lower in the permissive hypotension group (median 17.7 mg) compared to the usual care group (median 26.4 mg).

4. There was no significant increase in serious adverse events in the permissive hypotension group, suggesting the strategy is safe within the tested population.

5. A subgroup analysis suggested a potential mortality benefit among patients with pre-existing chronic hypertension, although this finding requires cautious interpretation due to the lack of adjustment for multiple comparisons.

Study Design

Design

RCT

Open-Label

Sample

2,463

Patients

Duration

90 days

Median

Setting

Multicenter, UK

Population Patients aged 65 years or older admitted to critical care units requiring vasopressors for vasodilatory hypotension.

Intervention Permissive hypotension strategy with a target mean arterial pressure of 60-65 mmHg while receiving vasopressors.

Comparator Usual care, with mean arterial pressure targets determined at the discretion of the treating clinician.

Outcome All-cause mortality at 90 days.

Study Limitations

• The study was open-label, which introduces potential bias in the management of vasopressor titration and co-interventions.

• The trial was powered to detect a 6% absolute risk reduction, and the observed difference of approximately 2.85% fell short of statistical significance, suggesting the study may have been underpowered for the observed effect size.

• The primary outcome analysis was unadjusted, and while an adjusted model showed a more favorable odds ratio (0.82; 95% CI, 0.68-0.98), this finding should be interpreted as hypothesis-generating.

• Generalizability is limited as the study population was exclusively patients aged 65 years and older, and results may not apply to younger patients or those with different types of shock.

• The control group (usual care) was not strictly standardized, reflecting a wide variation in clinical practice across the participating critical care units.

Clinical Significance

The study provides evidence that a more conservative 'permissive hypotension' approach (targeting a MAP of 60-65 mmHg) is a safe alternative to standard, often higher, blood pressure targets in older patients. While it did not reach the threshold for statistical superiority in 90-day mortality, it allows clinicians to reduce vasopressor use, which may mitigate potential harm associated with excessive vasoconstriction.

Historical Context

Prior to this trial, international guidelines, such as the 2012 Surviving Sepsis Campaign, recommended a minimum MAP target of 65 mmHg but often implicitly encouraged higher targets in the elderly due to concerns about organ perfusion. Previous trials (e.g., SEPSISPAM) and meta-analyses had hinted that higher MAP targets might actually be detrimental in certain populations, prompting the need for a dedicated, large-scale RCT to test the 'less is more' approach in the elderly.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the concept of 'autoregulation' explain the physiological basis for targeting a specific Mean Arterial Pressure (MAP) like 60-65 mmHg in critically ill patients?

Key Response

Autoregulation is the ability of organs (especially the brain and kidneys) to maintain constant blood flow despite changes in perfusion pressure. The 'lower limit' of autoregulation is typically around a MAP of 60-70 mmHg. If MAP drops below this threshold, flow becomes pressure-dependent, risking organ ischemia. The 65 Trial tested whether the lower end of this range (60-65 mmHg) was sufficient to maintain organ function in older adults compared to higher 'usual care' targets.

Resident

In an 80-year-old patient with septic shock and a history of chronic hypertension, does the 65 Trial support a lower MAP target, or should you aim higher to prevent Acute Kidney Injury (AKI)?

Key Response

Unlike the earlier SEPSISPAM trial, which suggested that patients with chronic hypertension might benefit from higher MAP targets (80-85 mmHg) to reduce AKI, the 65 Trial found that a permissive hypotension strategy (60-65 mmHg) was safe in older patients, including those with hypertension. There was no significant difference in the requirement for renal replacement therapy or 90-day mortality, suggesting that avoiding vasopressor toxicity may be as important as maintaining higher pressures in this demographic.

Fellow

The 65 Trial observed a reduction in total vasopressor exposure (dose and duration) in the intervention group. Discuss the potential 'catecholamine toxicity' mechanisms that a permissive hypotension strategy aims to mitigate in the geriatric population.

Key Response

Excessive vasopressors (catecholamines) in the elderly can lead to tachycardia, increased myocardial oxygen demand, stress-induced cardiomyopathy, digital ischemia, and immune modulation. By accepting a MAP of 60-65 mmHg, clinicians may avoid these iatrogenic harms. The trial's safety profile suggests that for many older patients, the risk of high-dose vasopressors outweighs the theoretical benefit of a slightly higher perfusion pressure.

Attending

Given that the primary outcome of 90-day mortality did not reach statistical significance (P=0.15) but the point estimate favored the intervention (OR 0.82), how should this trial influence your bedside teaching regarding 'usual care' for vasodilatory shock in the ICU?

Key Response

The trial provides high-level evidence that targeting a MAP of 60-65 mmHg is not harmful and successfully reduces the duration of vasopressor therapy. As a teaching point, it shifts the burden of proof: instead of asking 'why is the MAP so low?', we should ask 'what is the clinical indication for pushing the MAP above 65?' if there is no evidence of hypoperfusion (e.g., normal lactate, adequate mentation/urine output).

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The 65 Trial utilized a pragmatic, multicenter design. How might 'control group contamination' or 'practice drift'—where the usual care group's MAP targets move toward the intervention target—impact the study's power to detect a mortality difference?

Key Response

In pragmatic trials, clinicians in the 'usual care' group may be influenced by the study protocol or emerging trends toward lower MAP targets, narrowing the actual physiological difference between the two arms. This reduces the effect size and increases the risk of a Type II error. In the 65 Trial, the mean MAP in the usual care group was actually quite close to the intervention group in some centers, potentially diluting the observed benefit of the permissive strategy.

Journal Editor

The primary analysis used an unadjusted model, while the adjusted model (correcting for baseline variables) yielded a 95% CI that did not cross 1.0 (0.68-0.98). How would you weigh the editorial significance of a 'negative' primary result against a 'positive' secondary/adjusted analysis in this study?

Key Response

Editors must be cautious of 'p-hacking' or over-interpreting adjusted models when the primary ITT (Intention-To-Treat) analysis is non-significant. However, in the 65 Trial, the consistency of the point estimates across various sensitivity analyses suggests a robust signal of safety. The editorial significance lies in the trial's ability to potentially de-escalate a standard of care (aggressive pressors) that lacks a strong evidence base, even if the mortality benefit is not definitive.

Guideline Committee

The 2021 Surviving Sepsis Campaign guidelines recommend a MAP target of 65 mmHg. Based on the 65 Trial, should the committee consider a 'weak' recommendation for a lower range (60-65 mmHg) specifically for patients ≥65 years old?

Key Response

While the 65 Trial demonstrates safety for the 60-65 mmHg range, current guidelines (SSC 2021) maintain 65 mmHg as the 'floor.' The committee might not lower the target below 65 due to the lack of a statistically significant mortality benefit in the primary analysis, but they may use this data to strongly advise against higher targets (>70 mmHg) in older adults to avoid the adverse effects of prolonged vasopressor use, thereby refining the 'weak' recommendation for the 65 mmHg target.

Clinical Landscape

Noteworthy Related Trials

2014

SEPSISPAM Trial

n = 776 · NEJM

Tested

Higher mean arterial pressure target (80-85 mmHg)

Population

Patients with septic shock

Comparator

Lower mean arterial pressure target (65-70 mmHg)

Endpoint

28-day mortality

Key result: There was no significant difference in 28-day mortality between the high and low blood pressure targets.

2015

SEPSISPAM Subgroup Analysis

n = 776 · AJRCCM

Tested

Higher mean arterial pressure target (80-85 mmHg) in patients with chronic hypertension

Population

Septic shock patients with a history of chronic hypertension

Comparator

Lower mean arterial pressure target (65-70 mmHg)

Endpoint

Renal replacement therapy dependence at 28 days

Key result: Patients with chronic hypertension randomized to the higher target group had significantly lower rates of renal replacement therapy.

2020

OVATION Trial

n = 118 · JAMA Intern Med

Tested

Permissive hypotension (MAP 60-65 mmHg)

Population

Older critically ill patients with vasodilatory shock

Comparator

Standard care

Endpoint

Vasopressor-free days at day 28

Key result: Permissive hypotension was feasible and safe in older patients, potentially reducing vasopressor burden.

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