Importance Prehabilitation (prehab) programs are increasingly recognized for their potential to improve surgical outcomes. However, their efficacy remains debated, largely due to a lack of pathophysiologically-driven implementation and limited personalization.

Objective To determine the impact of personalized versus standard prehab on preoperative physical, cognitive, and immune function and postoperative outcomes.

Design, Setting, and Participants In this prospective, single-blinded, interventional trial conducted from October 2020 to April 2024 in a single academic medical center, 58 patients undergoing major elective surgery were randomized to standard (n=30) or personalized prehab (n=28) using block randomization.

Intervention The personalized group received weekly remote coaching tailored to individual progress in four domains (nutrition, physical activity, cognitive training, and mindfulness), while the standard group followed a paper-based program without individualized support.

Main Outcomes and Measures Primary clinical outcomes included cognitive assessments and physical performance measures, including the Wall Squat Test, Timed-up-and-go Test, 6-Minute Walk Test (6MWT). The primary immunological outcomes included major innate and adaptive immune cell frequencies and intracellular signaling responses measured using a 47-plex mass cytometry immunoassay.

Results Fifty-four of 58 patients completed the study (n=27 per group). The personalized group exhibited significant improvements in physical measures (e.g., 6MWT; p=0.03) and fewer severe postoperative complications (4 vs. 11 Clavien-Dindo grade >1; p=0.04). Multivariable modeling identified profound and cell-type specific immune alterations post-prehab compared to baseline (AUROC=0.88 [0.79, 0.97], p=2-06; leave-one-out cross-validation), including dampened pERK1/2 signaling in classical monocytes and myeloid-derived suppressor cells after interleukin (IL)-2,4,6 stimulation, and reduced pCREB signaling in Th1 cells. In contrast, the standard group showed only moderate clinical improvements and no immune changes (AUROC=0.63, p=0.11).

Conclusions and Relevance Our study demonstrates personalized prehab significantly altered the immunome before surgery, dampening inflammatory signaling responses previously implicated in the pathophysiology of key surgical outcomes, including surgical site infections and postoperative neurocognitive decline. These changes were accompanied by improved physical and cognitive function before surgery and decreased postoperative complications. Our findings support utilization of personalized prehab and provide an avenue for biologically-driven risk- stratification for patient selection, and individual tailoring of programs to optimize surgical readiness and recovery.

Trial Registration: NCT04498208

Question How do personalized prehabilitation programs modulate the peripheral immune system in patients undergoing major elective surgery?

Findings In a randomized trial, patients scheduled for major elective surgery received either personalized or standard prehabilitation. High-dimensional immune profiling with mass cytometry revealed profound and cell type-specific dampening of pro-inflammatory signaling responses in the personalized prehabilitation group (AUROC=0.88, n=27), but not in the standard group (AUROC=0.63, n=27). Patients in the personalized prehabilitation group also showed significant improvements in both physical and cognitive function, with significantly fewer severe postoperative complications (4 vs. 11).

Meaning Personalized prehabilitation dampens patients’ pre-operative inflammatory state and enhances recovery by improving physical and cognitive outcomes, suggesting tailored interventions may optimize surgical preparedness and reduce complications.

J.H., B.G., and F.V. are listed as inventors on a patent application (PCT/US2023/074903). J.H., B.G., D.G., and F.V. are advisory board members, BC is employed, and E.G. is a consultant at SurgeCare SAS. The remaining authors declare no competing interests.

NCT04498208

This work was supported by the Fondation des Gueules Cassees the Philippe Foundation the Societe Francaise d Anesthesie-Reanimation (SFAR) (AC) the Stanford Department of Anesthesiology Perioperative and Pain Medicine the Center for Human Systems Immunology NIH (1R35GM137936) (BG) and the Stanford Department of Surgery.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

It was conducted in accordance with the declaration of Helsinki approved by Stanford Institutional Review Board (IRB-57570) and registered in 2020 on ClinicalTrials.gov (NCT04498208)

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors