A comprehensive systematic review and meta-analysis evaluating randomized controlled trials has determined that perioperative remote ischemic conditioning does not offer a preventative effect against postoperative delirium or postoperative cognitive dysfunction. The study, synthesized by researchers including Kaden Lam, Bogna Anna Drozdowska, Ryan Rosentreter, Alyssa Coloso, and Aravind Ganesh, pooled findings across clinical trials to determine whether inducing transient ischemia in limbs could protect the brain during surgical interventions. Despite strong biological hypotheses and animal models suggesting neuroprotective pathways through the attenuation of systemic inflammation, the statistical synthesis of patient data across human surgical trials demonstrates no significant reduction in primary clinical neurocognitive complications.
Postoperative neurocognitive disorders represent common and feared clinical sequelae following major operations, particularly among older surgical populations. Postoperative delirium is recognized as a major public health concern affecting between 15% and 53% of patients aged 65 years and older, manifesting as acute confusion alongside distorted consciousness, altered attention, perception, memory impairments, and delirious behavior. In parallel, postoperative cognitive dysfunction manifests as an often subtle decline detectable from seven days after an operation, affecting approximately one in three older adults at one week post-surgery and persisting in one in one hundred patients at one year.
Given the immense burden placed on both individual patients and broader healthcare systems, clinicians and researchers have actively sought preventative strategies to mitigate these neurocognitive risks. Remote ischemic conditioning emerged as an appealing candidate therapy because it is non-invasive, low in cost, and easily administered using a standard blood pressure cuff to induce brief cycles of ischemia followed by reperfusion. Historically investigated to mitigate acute kidney injury and myocardial or cerebral infarction during cardiovascular and transplant operations, the therapy was increasingly proposed for neuroprotection. Preclinical rodent studies had demonstrated that limb ischemia cycles could attenuate neuroinflammation and oxidative stress pathways associated with surgical trauma and anesthetic exposure, while preliminary human investigations reported reductions in inflammatory markers such as tumor necrosis factor-alpha and S100B, as well as enhancements in dynamic cerebral autoregulation.
To rigorously evaluate the therapeutic claims surrounding this intervention, the investigative team established an exhaustive systematic review protocol registered in the PROSPERO database and conducted according to PRISMA reporting guidelines. Electronic databases including MEDLINE, Embase, and Web of Science were systematically queried from their inception through March 16, 2025. The authors established strict eligibility criteria requiring peer-reviewed randomized controlled trials that enrolled adult human participants aged 18 years or older undergoing surgical procedures with remote ischemic conditioning evaluated against a control arm. Independent investigators conducted screening, full-text evaluation, and risk of bias assessments using the Cochrane ROB-2 framework, synthesizing both binary diagnostic outcomes and continuous psychometric cognitive scores using DerSimonian-Laird random-effects models.
From an initial retrieval of 4,664 screened records, the systematic search identified 16 publications derived from 15 unique randomized controlled trials that encompassed a collective total of 2,912 surgical patients. Geographically, six trials originated from China, two from Germany, two from Korea, and one each from Croatia, Egypt, Russia, Ireland, and the United States of America. Across the included trials, the crude average participant age was 63.05 years with a standard deviation of 7.06 years in the remote ischemic conditioning cohorts and 62.58 years with a standard deviation of 7.89 years among control participants. Female patients constituted 28.91% of the overall trial population. In terms of clinical surgical settings, cardiac surgery predominated, accounting for nine trials representing 66.7% of the included literature, followed by two trials in cancer surgery, one in abdominal aortic aneurysm repair, one across general surgery requiring general anesthesia, one in total knee arthroplasty, and one in laparoscopic cholecystectomy.
The meta-analysis of primary clinical outcomes revealed that remote ischemic conditioning provided no statistically significant protection against acute delirium or persistent cognitive dysfunction. Ten individual studies reported either postoperative delirium or cognitive dysfunction, with observed baseline incidence ranges of 3.2% to 30.8% for delirium and 0.0% to 50.5% for cognitive dysfunction across diverse cohorts. While five of the six trials trended directionally toward favoring the intervention, the effect did not achieve statistical significance, and certainty in the evidence was rated as moderate according to GRADE criteria. Subgroup analyses among cardiac procedures yielded an odds ratio of 0.79 with a 95% confidence interval of 0.51 to 1.24, and meta-regression indicated no significant variation across surgery classifications.
Evaluations of postoperative cognitive dysfunction similarly failed to establish any significant therapeutic advantage associated with remote ischemic conditioning. For assessments conducted under 30 days post-surgery across five trials, the pooled odds ratio was 0.79 with a 95% confidence interval of 0.53 to 1.20 and low observed heterogeneity of 10.9%. Although an isolated subgroup analysis in laparoscopic cholecystectomy showed lower odds of early dysfunction with an odds ratio of 0.10, subgroup analyses in cardiac surgery showed no difference with an odds ratio of 0.80. Longer-term follow-up at 30 days or greater, reported across three clinical trials, yielded an odds ratio of 1.06 with a 95% confidence interval of 0.62 to 1.80 and zero percent measured heterogeneity. When pooling all follow-up intervals for cognitive dysfunction, the aggregate odds ratio remained non-significant at 0.87 with a 95% confidence interval of 0.65 to 1.18, leading to an overall GRADE certainty rating of low.
In secondary evaluations of standardized psychometric performance, the meta-analysis identified conflicting and largely inconclusive patterns across global and domain-specific cognitive batteries. On the Mini Mental State Examination, assessments conducted under 30 days showed no intergroup difference across four trials, producing a standardized mean difference of 0.11 with a 95% confidence interval from minus 0.11 to 0.32. Conversely, two cardiac surgery trials evaluating the examination at 30 days or beyond showed significantly higher scores among treated patients, yielding a standardized mean difference of 1.16 with a 95% confidence interval of 0.81 to 1.50. On the Montreal Cognitive Assessment evaluated within 30 days across two trials, treated participants scored moderately higher than controls, showing a standardized mean difference of 0.48 with a 95% confidence interval of 0.19 to 0.76.
Assessments targeting discrete cognitive domains such as executive functioning, visual processing speed, and verbal memory showed an almost universal lack of consistent clinical benefit. Across trials administering the Trail Making Test Part A, patients undergoing remote ischemic conditioning actually took slightly longer to complete the processing task within 30 days, generating a standardized mean difference of 0.28 with a 95% confidence interval of 0.07 to 0.48. No differences between arms were observed on Trail Making Test Part B, Digit Symbol Substitution Test scores, semantic or phonemic verbal fluency assessments, forward or backward digit span tests, or immediate and delayed verbal memory recall. Although slight performance gains were noted on Stroop test parts 1 and 2 at short-term follow-ups, with standardized mean differences of 0.38 and 0.26 respectively, overall domain-specific findings were deemed essentially neutral and heavily constrained by small study counts and methodological disparities.
The study authors documented several critical methodological limitations across the published literature that temper definitive clinical interpretations and underscore the need for standardized research frameworks. The risk of bias evaluation determined that only three included studies demonstrated a low risk of overall bias, while eleven carried some methodological concerns and two had a high risk of bias, particularly in randomization procedures and missing outcome data tracking. Furthermore, the substantial majority of trials were restricted to cardiac surgical settings, limiting generalizability across broader operative populations, while potential interaction effects involving propofol anesthesia, which has been cited as interfering with conditioning mechanisms, could not be isolated due to insufficient reporting. To establish whether remote ischemic conditioning holds genuine merit for specific surgical subgroups, future clinical investigations must adopt harmonized cognitive definitions, standardized multi-domain test batteries, and rigorous trial reporting.
Subject of Research: Meta-analysis evaluating remote ischemic conditioning for postoperative neurocognitive disorders
Article Title: Effects of perioperative remote ischemic conditioning on postoperative delirium and cognitive outcomes: a systematic review and meta-analysis of randomized controlled trials
Article References: Lam, K., Drozdowska, B. A., Rosentreter, R., Coloso, A., & Ganesh, A. (2026). Effects of perioperative remote ischemic conditioning on postoperative delirium and cognitive outcomes: a systematic review and meta-analysis of randomized controlled trials. Anesthesiology and Perioperative Science, 4(1), Article 19. https://doi.org/10.1007/s44254-026-00164-3
Image Credits: AI Generated
DOI: 10.1007/s44254-026-00164-3
Keywords: remote ischemic conditioning, postoperative delirium, postoperative cognitive dysfunction, systematic review, meta-analysis, anesthesiology, perioperative care, cardiac surgery, cognitive outcomes, clinical trials, Effects, perioperative
