Remote Ischemic Preconditioning (RIPC) in Non-Cardiac Surgery: What the PRINCE Trial Revealed

The PRINCE Trial, a large, multinational, double-blind study, found no reduction in perioperative myocardial injury (MINS) or relevant clinical outcomes at 30 days.

Key takeaways#

Concept and why it became promising

• RIPC (remote ischemic preconditioning) is a simple strategy: brief cycles of ischemia/reperfusion in a limb to try to "protect" vital organs, especially the myocardium, against perioperative ischemia.

What existed before PRINCE

• Before PRINCE, there were >70 randomized trials in non-cardiac surgery and meta-analyses suggesting benefit, but with many limitations (small size, biases, little blinding, and possible propofol interference).

What PRINCE showed and what it implies

• The PRINCE Trial, large, multinational, and double-blind, found no reduction in perioperative myocardial injury (MINS) or relevant clinical outcomes at 30 days.
• There were signs of harm/side effects: more petechiae in the cuff limb and more unplanned hospital readmission at 30 days in the RIPC group.
• The idea of "do it because it's cheap and non-invasive" loses strength: no proven benefit and possible adverse effects.

What is RIPC (remote ischemic preconditioning)?#

The concept of remote ischemic preconditioning (RIPC) is based on brief episodes of ischemia in a limb (arm or leg), capable of releasing humoral mediators that could "protect" vital organs, especially the myocardium, against ischemic episodes during and after surgery.

In practical terms: it's an intervention that seems "too simple not to try." And that's exactly why it needed a large, robust test.

Why study RIPC in non-cardiac surgery?#

Because the context is enormous and the problem is frequent.

• Approximately 300 million surgeries are performed worldwide every year.
• Even with technology, morbidity and mortality remain high, influenced by advanced age, multiple comorbidities, and frailty.
• Perioperative myocardial injury (MINS), characterized by elevated troponin after surgery, occurs in about 22% of patients in major surgeries, often without symptoms, and is associated with higher early and late mortality.

Hence the appeal of RIPC: a cheap, non-invasive intervention, with (theoretical) potential to change relevant outcomes.

What did we know before the PRINCE Trial?#

There were encouraging signs in animal models.

In coronary angioplasty and some cardiac scenarios, promising results also appeared.

In non-cardiac surgery, enthusiasm grew rapidly:

• >70 randomized trials of RIPC had already been published in non-cardiac surgical patients.
• Meta-analyses suggested troponin reduction, cardiovascular events, and even mortality and stroke.
• In 2017, a conference with 500 clinicians from 61 countries listed RIPC as one of the most promising perioperative interventions to reduce complications.

The "but" that remained standing

• Most studies were small and single-center,
• with biases, few blinded studies, and high statistical fragility,
• plus a recurring potential "villain": propofol, which may attenuate the preconditioning response.

What was missing was a large multinational, double-blind trial, with robust design, to answer the question that matters: does this work in the real world?

PRINCE Trial: the question the study tried to answer#

The question was straightforward:

In high-risk patients undergoing non-cardiac surgery under general anesthesia, does applying RIPC before surgery reduce the rate of perioperative myocardial injury?

And, as a bonus, it would also evaluate whether RIPC reduced:

• MI, stroke, acute kidney injury, ICU need, length of stay, and 30-day mortality.

Who was enrolled in PRINCE?#

• N = 1,213 patients
• 25 hospitals, in 8 countries, 3 continents
• Recruitment between 2015 and 2024

Main criteria

• > 50 years
• Intermediate or high-risk non-cardiac surgery, with general anesthesia
• Use of antiplatelet preoperatively (as an indicator of increased cardiovascular risk)

Typical clinical profile

• Many with ASA ≥ 3,
• hypertensive,
• many current or former smokers.

Randomization and blinding#

• Randomization 1:1 to:

  • "Real" RIPC
  • "Sham" RIPC (placebo)

• Double-blind: patients, anesthesiologists, surgeons, team, and outcome assessors didn't know which intervention was real.

• Execution was by a research member not involved in care, maintaining blinding.

How was RIPC applied in PRINCE?#

After general anesthesia induction:

• BP cuff on arm or leg.

RIPC group protocol

• 3 cycles of:

  • 5 min of ischemia (cuff at 200 mmHg)
  • 5 min of reperfusion (cuff deflated)

Sham group protocol

• Everything identical, but the cuff wasn't actually inflated (open valve to simulate the procedure)

Crucial detail: propofol prohibited

• Propofol was prohibited for induction and maintenance.
• This was a protocol requirement, precisely because there's evidence that propofol may block RIPC's protective effects.

The rest (drugs, maintenance technique, hemodynamic management) was at the anesthesiologist's discretion: pragmatic design.

What was measured?#

Primary outcome

• Perioperative myocardial injury (MINS): any troponin above the 99th percentile of the upper reference limit, in the first 3 days.

Secondary outcomes

• MI at 30 days
• Stroke at 30 days
• Acute kidney injury (KDIGO) at 7 days
• ICU need
• Length of stay
• All-cause mortality at 30 days

Sample size was calculated to detect an absolute reduction of 7% in myocardial injury incidence, with 80% power.

Final sample

• 2,318 patients recruited
• 1,217 included
• 1,213 analyzed (599 RIPC, 614 sham)

PRINCE Trial in numbers#

PRINCE Trial results#

Primary outcome: troponin (MINS)

• Perioperative myocardial injury:

  • RIPC: 38.0% (215/566)
  • Sham: 37.4% (223/596)
  • RR = 1.02 (95% CI 0.88-1.18; p = 0.84)

Clinical translation: no difference, not even a trend toward benefit.

Per-protocol, as-treated, and various subanalyses all reached the same result.

Exploratory subgroup (concerning)

• Patients who received RIPC on the leg had more myocardial injury than the sham group.

Secondary outcomes

• MI at 30 days: 1.5% (RIPC) vs 2.6% (sham)
• Stroke: rare, no difference
• Acute kidney injury at 7 days: 2.8% vs 2.6%
• ICU need: 28.8% vs 26.4%
• Length of stay: median 5 vs 5 days
• 30-day mortality: 1.7% vs 1.3%

There was also no difference in troponin >5x the limit (cutoff associated with worse outcomes in other cohorts).

Results and safety: RIPC vs sham#

Safety: the "does no harm" assumption falls apart#

Overall, RIPC was well tolerated, but there were:

• Petechiae in the cuff limb:

  • 1.7% (RIPC) vs 0.2% (sham) - RR 10.2; p = 0.01

• Unplanned hospital readmission at 30 days:

  • 6.0% (RIPC) vs 3.5% (sham) - RR 1.74 (95% CI 1.02-2.99)

In other words: the idea that RIPC would be a "no harm" intervention with likely benefit has lost support.

Is PRINCE a robust study?#

Strengths

• Largest RCT of RIPC in non-cardiac surgery to date (1,213 patients)
• Multicenter, multinational, three continents
• Double-blind, with well-structured sham
• Standardized procedure: 3 cycles of 5 min at 200 mmHg
• 95% with troponin collected in first 3 days
• Avoided propofol, a potential relevant confounding factor

Limitations

• Did not measure preoperative troponin
• Did not measure biomarkers of cerebral or pulmonary injury
• Population more similar to high-income European countries; extrapolation requires caution
• RIPC applied after induction and immediately before surgery; did not test earlier RIPC (e.g., 24h before)

Take-home: what changes in practice#

1. PRINCE is the largest RCT on RIPC in non-cardiac surgery to date: 1,213 patients, 25 hospitals, 8 countries, double-blind and sham-controlled.
2. RIPC DID NOT reduce MINS (troponin), nor MI, nor stroke, nor AKI, nor ICU use, nor 30-day mortality.
3. There were more petechiae in the limb and more unplanned hospital readmission at 30 days in the RIPC group.
4. The "let's do it because it costs nothing" thesis loses strength: no proven benefit and possible side effects.

Future research lines may explore:

• Earlier RIPC (24h before),
• other protocols (4 cycles, different pressures),
• specific populations (even sicker subgroups),
• other outcomes (delirium, renal/cerebral function, etc.).

But that's a research domain, not clinical routine.

Want to turn perioperative evidence into faster decisions?#

When a "promising" topic falls in a large RCT (like PRINCE), the hard part isn't knowing it came out. It's managing to organize the impact on your practice, without opening dozens of tabs, PDFs, and scattered discussions.

In the AnestCopilot ecosystem, Deep Evidence helps review literature and synthesize findings at different depth levels, and other tools can support perioperative reasoning in common day-to-day situations (always as decision support, without replacing clinical judgment).

Related reading#

• AI Revolutionizing Anesthesiology: From Machine Learning to AnestCopilot
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• HES 6% in Surgical Fluid Therapy: Does PHOENICS Rewrite the Story?