Risk-Stratified Proactive Blood Pressure Management Fails to Improve Long-Term Functional Recovery After Noncardiac Surgery: Insights from the PRETREAT Trial

Highlights

No Significant Difference in Functional Disability

The proactive management of intraoperative blood pressure (BP), using risk-stratified targets as high as 90 mm Hg, did not significantly improve functional disability at 6 months compared to standard care (mean difference -0.5 on the WHODAS 2.0 scale).

Early Termination for Futility

Following an interim analysis of 3,247 patients, the trial was stopped early because it was determined that achieving the primary outcome of a 5-point improvement in functional disability was statistically improbable.

Consistency Across Secondary Endpoints

There were no significant differences observed across 23 secondary outcomes, including postoperative complications, quality of life, and mortality, suggesting that higher blood pressure targets may not offer a clear advantage in general surgical populations.

Background: The Challenge of Perioperative Hypotension

Intraoperative hypotension (IOH) is one of the most common and potentially modifiable risk factors in the perioperative period. For decades, observational data have consistently linked even brief episodes of low mean arterial pressure (MAP) to adverse outcomes, including acute kidney injury (AKI), myocardial injury after noncardiac surgery (MINS), and postoperative stroke. Traditionally, a MAP threshold of less than 65 mm Hg has been considered the ‘danger zone’ where organ autoregulation fails and ischemic injury begins.

However, the clinical community remains divided on the optimal strategy for managing BP. Should clinicians be ‘reactive’—treating hypotension only when it crosses a universal threshold—or ‘proactive,’ attempting to maintain higher, individualized pressures based on a patient’s specific risk profile? Previous studies, such as the INPRESS trial, suggested that individualized BP targets could reduce postoperative organ dysfunction. Yet, larger pragmatic trials have struggled to confirm whether these physiological benefits translate into long-term functional recovery for the patient. The PRETREAT trial was designed to address this critical gap by shifting the focus from short-term biochemical markers to long-term functional disability.

Study Design: The PRETREAT Methodology

The PRETREAT trial (Proactive vs Reactive Treatment of Hypotension During Surgery) was a multicenter, randomized clinical trial conducted at two tertiary hospitals in the Netherlands. The study enrolled 3,247 adults undergoing elective noncardiac surgery with an expected duration of at least 60 minutes.

Risk-Stratified Intervention

Patients in the proactive group were stratified into three categories based on their baseline risk for intraoperative hypotension:
1. Low Risk: Target MAP of 70 mm Hg or higher.
2. Intermediate Risk: Target MAP of 80 mm Hg or higher.
3. High Risk: Target MAP of 90 mm Hg or higher.

In this group, anesthesiologists were encouraged to use vasopressors and fluid boluses preemptively to maintain these elevated targets. In contrast, the standard care group followed usual management, where the primary goal was typically to avoid a MAP below 65 mm Hg, with no higher predefined targets mandated.

Primary and Secondary Endpoints

The primary outcome was functional disability at 6 months post-surgery, measured by the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). The WHODAS scale ranges from 0 to 100, where higher scores reflect greater disability. The researchers defined a minimally clinically important difference (MCID) as 5 points. Secondary outcomes included health-related quality of life (EQ-5D-5L), major postoperative complications, and all-cause mortality.

Key Findings: Futility and Functional Outcomes

Despite the rigorous stratification and proactive intervention, the results of the PRETREAT trial were largely neutral. The trial was halted after reaching 65% of its planned enrollment (3,247 of 5,000 patients) due to futility.

Functional Disability Results

At the 6-month follow-up, the mean WHODAS score in the proactive group was 17.7, compared to 18.2 in the standard care group. The mean difference of -0.5 (95% credible interval, -1.9 to 0.9) fell far short of the 5-point difference required to meet clinical significance. Baseline scores were balanced between groups, and the trajectory of recovery was nearly identical.

Secondary Outcomes and Safety

Analysis of the 23 secondary outcomes revealed no statistically significant differences. Specifically, the incidence of major complications (such as myocardial infarction or renal failure) and mortality rates did not differ between those managed with aggressive BP targets and those receiving standard care. Interestingly, the proactive group received significantly higher doses of vasopressors and fluids to reach their targets, yet this increased intervention did not result in improved patient-centered outcomes.

Expert Commentary: Moving Beyond Pressure Targets

The findings of the PRETREAT trial provide a sobering perspective on the limits of intraoperative hemodynamic optimization. While it is physiologically sound to believe that higher perfusion pressures protect organs, the translation of this physiology into a measurable reduction in long-term disability remains elusive.

The Problem of the ‘Universal Threshold’

One possible explanation for the trial’s outcome is that the ‘standard care’ group was already managed quite well. In modern anesthesia practice, avoiding a MAP of 65 mm Hg is standard. If the standard care group rarely experienced prolonged or deep hypotension, the incremental benefit of pushing the MAP to 80 or 90 mm Hg might be negligible, especially if it requires excessive vasopressor use, which carries its own risks of vasoconstriction and tissue ischemia.

Functional vs. Biochemical Endpoints

There is also the question of whether WHODAS 2.0 is the right lens through which to view intraoperative management. Functional disability is influenced by myriad factors—surgical technique, preoperative frailty, postoperative rehabilitation, and underlying comorbidities. The ‘signal’ from a few hours of blood pressure management during surgery may simply be drowned out by the ‘noise’ of these other variables over a six-month period.

Individualization vs. Stratification

Unlike the INPRESS trial, which used the patient’s own baseline resting BP as a target, PRETREAT used risk-based categories. Some experts argue that 90 mm Hg might be ‘too high’ for some high-risk patients and ‘not high enough’ for others. The lack of benefit in PRETREAT suggests that categorical risk-stratification may not be granular enough to improve long-term outcomes.

Conclusion: Implications for Clinical Practice

For the practicing anesthesiologist, the PRETREAT trial reinforces the adequacy of current standard-of-care practices. While preventing hypotension remains a cornerstone of perioperative safety, there is currently no high-level evidence to support the routine use of aggressive, risk-stratified MAP targets (up to 90 mm Hg) to improve long-term functional recovery.

Clinicians should continue to prioritize the avoidance of MAP < 65 mm Hg and consider individual patient factors, but they can do so without the pressure to maintain artificially high targets that necessitate increased pharmacological intervention. Future research may need to focus on more precise, autoregulation-based monitoring rather than fixed or categorical pressure goals.

Funding and Trial Registration

This study was funded by the Netherlands Organisation for Health Research and Development (ZonMw). The trial was registered with the Overview of Medical Research in the Netherlands (CCMO): NL-OMON55117.

References

1. Kant M, van Klei WA, Hollmann MW, et al. Proactive vs Reactive Treatment of Hypotension During Surgery: The PRETREAT Randomized Clinical Trial. JAMA. 2025;334(21):1905-1914. doi:10.1001/jama.2025.18007.
2. Futier E, Lefrant JY, Guinot PG, et al. Effect of Individualized vs Standard Blood Pressure Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial. JAMA. 2017;318(14):1346-1357.
3. Sessler DI, Khanna AK. Perioperative Myocardial Injury and the Contribution of Hypotension. Intensive Care Med. 2018;44(6):811-822.
4. Wesselink EM, Kappen TH, Torn IA, et al. Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review. Br J Anaesth. 2018;121(4):706-721.