Do Chest Compressions Benefit the Brain Beyond Restoring Circulation? ROSC-Mediated and ROSC-Independent Pathways of Bystander CPR After Out-of-Hospital Cardiac Arrest

Background/Objectives: Bystander cardiopulmonary resuscitation (CPR) improves outcome after out-of-hospital cardiac arrest (OHCA), but whether its neurological benefit operates solely through prehospital return of spontaneous circulation (ROSC) is unresolved. We quantified the mediated and unmediated components. Methods: Retrospective cohort study of the Korean nationwide OHCA registry (2009–2024) in adults with cardiac or respiratory arrest, excluding arrests witnessed by on-duty personnel. The primary outcome was favorable neurological survival (Cerebral Performance Category 1–2 at discharge) defined across the whole cohort; prehospital ROSC was the mediator. Effects were decomposed with logistic models, including an exposure-by-mediator interaction. Results: Among 80,784 patients, 59,982 (74.2%) received bystander CPR. The natural direct effect was +1.24 percentage points (95% CI 0.97 to 1.51). With prehospital ROSC fixed by intervention at not achieved—for everyone, not only for patients observed to lack it—the controlled direct effect was +0.65 (0.41 to 0.85) and +0.70 (0.46 to 0.94; E-value 2.43, lower confidence limit 1.92) on restriction to 2016–2024. The total effect was +5.24 points (4.85 to 5.60), 76.4% of it ROSC-mediated. No survival effect was demonstrable at that value (+0.25, −0.14 to 0.61), and adjustment for initial rhythm left the neurological estimate indistinguishable from zero (+0.36, −0.02 to 0.69). Conclusions: A small component of the neurological benefit may lie outside the prehospital ROSC pathway—not outside restored circulation altogether since such survivors regained circulation in hospital—though most was ROSC-mediated. It is not established: an unmeasured confounder of moderate strength, or initial rhythm acting as a confounder rather than a mediator, would account for it. The estimates apply to events with ascertained bystander-CPR status, undocumented in 70% of otherwise eligible events. Prehospital ROSC may nonetheless understate the value of bystander response.