JAMA March 10, 2020

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

François Lamontagne, Alvin Richards-Belle, Karen Thomas, David A. Harrison, et al. (65 Trial Investigators)

Bottom Line

In critically ill adults aged 65 years or older with vasodilatory hypotension, a permissive hypotension strategy targeting a MAP of 60 to 65 mmHg compared with usual care safely reduced vasopressor exposure but did not result in a statistically significant reduction in 90-day mortality.

Key Findings

1. Permissive hypotension significantly reduced overall vasopressor exposure compared to usual care, with a shorter median duration (33 hours vs 38 hours; absolute difference -5.0 hours) and lower median total norepinephrine-equivalent dose (17.7 mg vs 26.4 mg; absolute difference -8.7 mg).

2. For the primary outcome, 90-day all-cause mortality was 41.0% in the permissive hypotension group compared to 43.8% in the usual care group (absolute risk difference -2.85% [95% CI, -6.75% to 1.05%]; P = 0.15; unadjusted relative risk 0.93).

3. In a prespecified secondary analysis adjusting for baseline variables, permissive hypotension was associated with significantly lower 90-day mortality (adjusted Odds Ratio 0.82 [95% CI, 0.68 to 0.98]).

4. There was no significant difference in the incidence of serious adverse events (6.2% permissive vs 5.8% usual care), including comparable rates of acute renal failure (3.2% vs 2.5%) and supraventricular arrhythmias (0.9% vs 1.0%).

Study Design

Design

RCT

Open-Label

Sample

2,600

Patients

Duration

90 days

Median

Setting

65 ICUs, UK

Population Critically ill adults aged 65 years or older receiving a vasopressor infusion for vasodilatory hypotension (with adequate fluid resuscitation) for less than 6 hours, who were expected to continue requiring vasopressors for at least 6 more hours.

Intervention Permissive hypotension strategy where clinicians titrated vasopressors to strictly target a mean arterial pressure (MAP) of 60 to 65 mmHg.

Comparator Usual care, in which MAP targets and vasopressor weaning were managed at the treating clinician's discretion (typically targeting >65 mmHg).

Outcome All-cause mortality at 90 days after randomization.

Study Limitations

• The open-label design allowed treating clinicians to be aware of group assignments, which may have introduced performance bias and influenced fluid resuscitation or co-intervention practices.

• The primary unadjusted analysis did not cross the threshold for statistical significance, meaning the nominally significant adjusted outcome should be considered hypothesis-generating rather than definitive.

• A slight baseline imbalance existed between the groups, with a higher proportion of patients in the permissive hypotension group being dependent on assistance for activities of daily living.

• Loss to follow-up and withdrawn consent led to approximately 5% of the randomized 2,600 patients being excluded from the primary outcome analysis.

Clinical Significance

The 65 Trial establishes that tolerating a slightly lower mean arterial pressure (60-65 mmHg) in older ICU patients with vasodilatory shock is safe, limits exposure to potentially toxic exogenous catecholamines, and does not increase the risk of acute renal failure or fatal arrhythmias. While not proving a definitive survival benefit in its primary unadjusted analysis, it strongly supports a 'less is more' physiological approach, suggesting clinicians do not need to reflexively escalate vasopressors to strictly maintain standard higher MAP targets in patients aged 65 and older.

Historical Context

Historically, guidelines like the Surviving Sepsis Campaign recommended an initial target MAP of 65 mmHg for septic shock, though in routine practice, 'overshoot' often meant patients were maintained at much higher pressures. Two earlier major trials (SEPSISPAM and OVATION) evaluated higher vs. lower MAP targets and demonstrated no overall mortality benefit for higher targets, but their subgroup analyses suggested that higher MAP targets might paradoxically increase mortality in older patients (age >65) due to arrhythmias and excess vasoconstriction. The 65 Trial was directly designed to test this hypothesis, investigating whether intentionally reducing vasopressor doses through permissive hypotension would improve outcomes in this vulnerable elderly demographic.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the physiological consequences of using high doses of alpha-1 agonists like norepinephrine in older adults, and how does this provide a pathophysiological rationale for the 65 Trial's hypothesis?

Key Response

Older adults frequently have age-related cardiovascular changes, such as diastolic dysfunction, stiffer vasculature, and occult coronary artery disease. High-dose vasopressors increase afterload and myocardial oxygen demand, potentially decreasing stroke volume and triggering myocardial ischemia or arrhythmias. The 65 Trial hypothesized that sparing older patients from these deleterious catecholamine effects via permissive hypotension might improve mortality.

Resident

Given the results of the 65 Trial, if you are cross-covering the ICU and an 80-year-old septic patient on norepinephrine has a MAP of 62 mmHg, what clinical parameters should you assess before deciding whether to uptitrate the vasopressor?

Key Response

The trial demonstrated that a MAP of 60 to 65 mmHg is generally safe and doesn't increase mortality in older adults. Residents should learn to look beyond the isolated MAP number and assess markers of end-organ perfusion (e.g., capillary refill, urine output, mentation, lactate) before reflexively increasing vasopressors to hit a strict 65 mmHg target, thereby avoiding unnecessary catecholamine toxicity.

Fellow

The 65 Trial found no significant difference in rates of acute kidney injury or requirement for renal replacement therapy between the permissive hypotension and usual care groups. How do you reconcile this with the traditional concept of renal autoregulation and the historical belief that older patients need higher MAPs to perfuse their potentially sclerotic kidneys?

Key Response

Historically, intensivists targeted higher MAPs in older adults assuming a right-shifted renal autoregulation curve due to chronic hypertension. However, this trial suggests that the theoretical macro-hemodynamic benefits of higher MAP are offset by catecholamine-induced microvascular renal vasoconstriction and venous congestion. Fellows must understand the delicate balance between systemic driving pressure and microcirculatory flow.

Attending

The 65 Trial showed a reduction in vasopressor exposure without a statistically significant mortality benefit, yet many intensivists view this as a practice-changing 'positive' trial. How do you utilize 'negative' primary outcome trials in critical care to teach trainees about the value of de-escalation and minimizing iatrogenic harm?

Key Response

While the primary outcome of 90-day mortality was neutral, proving the safety of a lower MAP target is highly valuable clinically. It empowers clinicians to accept 'good enough' hemodynamics, which facilitates earlier vasopressor weaning, shorter ICU stays, and minimization of iatrogenic harm from lines and drugs. Attendings can use this to teach that 'less is more' is often a valid and successful clinical strategy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The 65 Trial used a pragmatic, unblinded design where usual care was allowed to vary according to local practice. How does this 'usual care' control group introduce potential performance bias or contamination, and what statistical methods are required to verify the true separation of hemodynamic profiles between the two arms?

Key Response

In unblinded pragmatic trials, the control group's care can be influenced by the trial's existence, a phenomenon where clinicians in the usual care arm might tolerate lower MAPs than they historically would (contamination). Researchers must meticulously analyze the time-weighted average MAP and area-under-the-curve for vasopressor doses to verify if the biological separation was actually sufficient to adequately power the hypothesis test.

Journal Editor

A major methodological critique of the 65 Trial is the relatively small separation in mean MAP between the permissive hypotension group and the usual care group (often just a few mmHg difference). As an editor evaluating this manuscript, how does this narrow physiological separation affect the internal validity and the trial's ability to definitively answer whether a MAP of 60 is superior to a MAP of 70?

Key Response

A critical reviewer would flag that if the control group's MAP was close to 65 mmHg anyway, the trial might be underpowered to detect a difference because the interventions weren't distinct enough. The trial actually tests a clinical strategy (a permissive target of 60-65) versus real-world usual care (which often naturally hovers around 65-70), making it a trial of behavioral strategy rather than a strict physiological test of disparate MAP levels.

Guideline Committee

The Surviving Sepsis Campaign (SSC) guidelines traditionally recommend a uniform initial MAP target of 65 mmHg. Based on the findings of the 65 Trial, should the SSC guidelines be updated to formally recommend an age-based or personalized MAP target, and what level of evidence does this trial provide for such a recommendation?

Key Response

The SSC currently suggests an initial target of 65 mmHg with a strong recommendation based on moderate quality evidence. The 65 Trial provides high-quality RCT evidence that targeting 60-65 mmHg is safe in patients over 65 and reduces vasopressor use. The committee must debate whether to create a conditional recommendation for a lower target (60-65) in older adults to spare vasopressor toxicity, officially shifting away from a 'one size fits all' minimum threshold.

Clinical Landscape

Noteworthy Related Trials

2008

VASST

n = 778 · NEJM

Tested

Low-dose vasopressin

Population

Patients with septic shock receiving norepinephrine

Comparator

Norepinephrine alone

Endpoint

28-day mortality

Key result: The addition of vasopressin did not significantly reduce 28-day mortality overall, though it successfully reduced norepinephrine requirements.

2014

SEPSISPAM Trial

n = 776 · NEJM

Tested

High mean arterial pressure target (80-85 mmHg)

Population

Patients with septic shock requiring vasopressors

Comparator

Low mean arterial pressure target (65-70 mmHg)

Endpoint

28-day mortality

Key result: Targeting a higher MAP did not improve 28-day mortality but was associated with an increased risk of new-onset atrial fibrillation.

2017

ATHOS-3 Trial

n = 321 · NEJM

Tested

Intravenous angiotensin II

Population

Patients with catecholamine-resistant vasodilatory shock

Comparator

Placebo

Endpoint

Mean arterial pressure response at 3 hours

Key result: Angiotensin II effectively increased blood pressure and allowed for a rapid reduction in the doses of standard background vasopressors.

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