Hausenloy, Derek J

Pang, Raymand

Robertson, Nicola J

English

UCL Discovery

COMMENT OPENRemote ischaemic post conditioning in NE: A feasible andsimple paradigm for self-protection in the brain?Nicola J. Robertson 1,2✉, Raymand Pang1 and Derek J. Hausenloy3,4,5,6© The Author(s) 2025Pediatric Research; https://doi.org/10.1038/s41390-025-03806-7Remote ischaemic post conditioning (RIPostC) has significantpotential as a simple, non-invasive and effective treatment toreduce neurodevelopmental impairment (NDI) in babies withmoderate-severe hypoxic ischaemic encephalopathy (HIE). In therecent publication by Lo and colleagues, a prospective, safety anddose escalation study of RIPostC is described in 32 babies with HIEundergoing hypothermia (HT).1 All patients received the desig-nated RIPostC therapy without interruption or delay. There wereno adverse events related to pain, vascular, cutaneous, muscularor neural safety effects. This study is an important step towardsusing RIPostC as a potential therapeutic intervention for babieswith HIE, establishing the critical safety and feasibility datanecessary for the design of future studies to investigate thepotential efficacy of RIPostC to reduce NDI. However, before phaseII clinical trials of RIPostC are considered in HIE, there is much tolearn about the optimal RIPostC protocol or “RIPostC dose” fromother conditions and from preclinical models.While therapeutic HT improves survival without disability aftermoderate-severe HIE and remains the cornerstone treatment forsuspected HIE, it is concerning that not all babies are protected inhigh-income settings2 and that HT is not beneficial in many low-and mid- income countries (LMIC).3,4 Clearly other therapies areneeded to both augment HT and provide an alternative treatmentto HT for HIE. Unlike other potential therapies for HIE which mayrequire cold chain storage (e.g. erythropoietin, stem cells) orintravenous access (e.g. melatonin, caffeine, azithromycin), theRIPostC intervention uses readily available neonatal equipment(an appropriately sized blood pressure cuff), the intervention maybe administered by medical or nursing staff, and it can be readilyimplemented in LMIC.RIPostC is a manoeuvre that creates transient cycles of ischemiaand reperfusion (I-R) to a remote site (e.g. limb).5 The goal is toprotect the organ exposed to ischaemia, such as the brain, fromfurther injury by inducing non-lethal ischemia in the remote site.The typical RIPostC intervention consists of 5 cycles of 5 minsischaemia and 5mins reperfusion using a blood pressure cuffinflated to supra-systolic pressure. RIPostC evolved from ischaemicpreconditioning, discovered in 1986 by Murry6 in the myocardium;subsequently Kitagawa described ischaemic tolerance in thebrain.7RIPostC likely exerts neuroprotection through several over-lapping mechanisms involving neuronal, humoral, and systemiceffects.8,9 In the neuronal pathway (Fig. 1), the activation ofafferent nerves and the release of neuropeptides at the site ofRIPostC act on the efferent nerves at the larger site of ischemia tooffer protection.8 The humoral pathway involves the release ofhydrophobic factors that travel from the site of RIC to the site ofischemia for protection.8,9 Adenosine, bradykinin-2, opioids,glucagon-like peptides and Stromal Cell Derived Factor-1a arepotential mediators.8,10,11 The systemic pathway involves themodification of the immune system by suppression of proin-flammatory genes encoding proteins involved in leucocytechemotaxis, adhesion, migration, and exocytosis,8 as well promot-ing microglia/macrophage transfer from M1 to M2 phenotype.12PRECLINICAL STUDIESThere is strong preclinical support for the efficacy of RIPostC toimprove neurological outcomes after cerebral ischaemia acrossmultiple species. These studies suggest protection by RIPostCeven with a delay of 3-6 h, although studies vary.13,14 The pigletmodel has been used to investigate RIPostC using magneticresonance spectroscopy (MRS) biomarkers. In 2015, Robertson andcolleagues reported robust protection of the white matter at 48 hwith four 10min cycles of bilateral lower limb I-R immediatelyafter HI.15 Subsequent studies in the piglet have been lessreassuring of RIPostC efficacy;16,17 this may be related to theseveral factors including “RIPostC dose and duration” as only onetreatment cycle was administered with a 1 h RIPostC delay.There is much that we can learn from other conditions toenhance the clinical translation of RIPostC for the treatment of HIE.RIPostC is gathering momentum as a potential therapy in adultstroke, traumatic brain injury (TBI) and necrotizing enterocolitis(NEC) in phase II and III clinical trials.ADULT STROKEA recent Phase III clinical trial in adults with acute moderateischaemic stroke (RICAMIS trial-including 1893 patients from 55hospital in China) observed an improved chance of excellentoutcome at 90 days with RIPostC administered after the ischaemicinsult.18 The intensity, duration and patient selection of theRIPostC intervention is a vital factor; in the RICAMIS trial, treatmentwith RIPostC was performed twice daily for 2 weeks within 48 h ofReceived: 11 November 2024 Accepted: 12 December 20241Institute for Women’s Health, University College London, London, UK. 2Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 3The Hatter CardiovascularInstitute, University College London, London, UK. 4National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore. 5Cardiovascular & MetabolicDisorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore. 6Yong Loo Lin School of Medicine, National University Singapore, Singapore,Singapore. ✉email: n.robertson@ucl.ac.ukwww.nature.com/pr1234567890();,:symptoms as an adjunct to routine treatment, compared withroutine treatment alone.18 The previously observed heterogenouseffects of RIPostC are likely secondary to patient selection andRIPostC implementation.18–20 Other studies support the conceptthat a longer duration of RIPostC may exert a more neuroprotec-tive effect. For example, RIPostC treatment twice daily for 2 weeksor until discharge with a mean duration of 11.2 days wasneuroprotective.19TRAUMATIC BRAIN INJURY (TBI)In a clinical trial of 84 patients with traumatic brain injury, asynergistic effect of head cooling and one course of RIPostC wasobserved with improved clinical outcomes compared to groupswho received either separately.21 The authors also suggest thatrepeated courses of RIPostC might improve outcomes further.NECROTIZING ENTEROCOLITIS (NEC)The clinical translation of RIPostC for NEC in preterm babies isinspirational. Preclinical studies in rat pups demonstrated thatRIPostC improved blood flow to the intestine, reduced theintestinal damage of experimental NEC and prolonged survival.22A recent Phase I safety study demonstrated that RIPostC (4 cyclesof I-R repeated on two consecutive days early in the NEC course)was safe in preterm infants with NEC.23 A phase II feasibility RCTinvolving 12 centres in 6 countries is underway, to investigate thefeasibility of RIPostC as a treatment for early-stage NEC in pretermneonates.Considering the knowledge so far from clinical and preclinicalstudies in RIPostC, it is likely that the intervention needs to be“topped up” during the evolving phase of secondary energyfailure after hypoxia ischaemia; hence repeated RIPostC courses(every 12–24 h) would be needed during the subacute phase (1st4–7 days) in HIE for optimal benefit. It is also possible that longer-term RIPostC might ameliorate the continuing inflammatorydysregulation associated with tertiary brain injury during theweeks and months after HIE.24 For example, in adult stroke, alonger duration of RIPostC treatment (more than 300 days) waseffective for secondary stroke prevention.25 There is also evidencethat RIPostC performed on increased muscle mass leads toimproved outcomes, suggesting that RIPostC in two limbs wouldbe better than RIPostC in one limb.26OPPORTUNITIES AND CHALLENGES OF RIPOSTC FORTREATMENT OF HIERIPostC triggers endogenous protective pathways in distantorgans such as the kidney, heart and brain, and represents anexciting new paradigm in neonatal neuroprotection. It isimperative that preclinical studies urgently define the optimal“RIPostC dose” after HI and that sensitive and specific biomarkersof RIPostC are discovered and validated. This will inform thedesign of future clinical trials in babies with HIE and ensure thatthe full potential of endogenous brain protection from RIPostC canbe exploited. If RIPostC were to reduce NDI in HIE in clinical trials(with and without HT), this treatment could be rolled out withrelative ease and lead to significant widespread benefit.TransmissionInitiation TransductionNeuronalHumoralSystemicRIPostC (one course)Optimal dose?5 min ischaemia5 min reperfusionRepeated x5Likely to need RIPostCcourse repeated every 12hto cover the period ofsecondary energy failureand cooling (4–7 days)Suppression ofproinflammatory genes andpromoting microglia/macrophage transfer from M1to M2 phenotypeRelease of factors e.g.adenosine, bradykinin-2,opioids, glucagon-like peptidesand stromal cell derivedfactor-1a. Converge onmitochondria (prosurvivalkinases, reduce ROS)Activation of afferent nerves atsite of RIPostC releaseneuropeptides which act onbrain (the area of indexischaemia)Increased cerebral blood flowABCFig. 1 Possible mechanisms through which the RIPostC signal is initiated, transmitted and transduced into brain protection in babieswith HIE. Initiation: The optimal dose of RIPostC (course and number of courses) is unknown although there is evidence that RIPostC needs tobe repeated during the injury cascade for optimal benefit. This may span 4-7 days in the newborn with HIE to cover the period of secondaryenergy failure. Transmission: Transmission of the RIPostC signal is through neuronal, humoral and systemic pathways which converge on themitochondria to reduced ROS and improve mitochondrial metabolism. RIPostC has been observed to increase cerebral blood flow.Transduction: These pathways combine to lead to potential beneficial effects on the index organ (brain) in HIE.N.J. Robertson et al.2Pediatric ResearchREFERENCES1. Lo, E. et al. Remote ischemic post-conditioning for neonatal encephalopathy:a safety and feasibility trial. Pediatr. Res. https://doi.org/10.1038/s41390-024-03625-2 (2024).2. Schreglmann, M., Ground, A., Vollmer, B. & Johnson, M. J. Systematic review: long-term cognitive and behavioural outcomes of neonatal hypoxic-ischaemic ence-phalopathy in children without cerebral palsy. Acta Paediatr. 109, 20–30 (2020).3. Robertson, N. J. et al. Therapeutic hypothermia for birth asphyxia in low-resourcesettings: a pilot randomised controlled trial. Lancet 372, 801–803 (2008).4. Thayyil, S. et al. HELIX consortium. Hypothermia for moderate or severe neonatalencephalopathy in low-income and middle-income countries (HELIX): a rando-mised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob. Health 9,e1273–e1285 (2021).5. Lu, M., Wang, Y., Ren, H., Yin, X. & Li, H. Research progress on the mechanism ofaction and clinical application of remote ischemic post-conditioning for acuteischemic stroke. Clin. Neurol. Neurosurg. 244, 108397 (2024).6. Murry, C. E., Jennings, R. B. & Reimer, K. A. Preconditioning with ischemia: a delayof lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136 (1986).7. Kitagawa, K. et al. Ischemic tolerance’ phenomenon found in the brain. Brain Res528, 21–24 (1990).8. Lim, S. Y. & Hausenloy, D. J. Remote ischemic conditioning: from bench tobedside. Front Physiol. 3, 27 (2012).9. Hess, D. C. et al. Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat. Rev. Neurol. 11, 698–710 (2015).10. Erbil, D. et al. GLP-1’s role in neuroprotection: a systematic review. Brain Inj. 33,734–819 (2019).11. Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury bythe stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc.Natl Acad. Sci. USA 101, 18117–18122 (2004).12. Han, D. et al. Remote Limb Ischemic Postconditioning Protects against IschemicStroke via Modulating Microglia/Macrophage Polarization in Mice. J. Immunol.Res. 2021, 6688053 (2021).13. Zhou, Y. et al. Remote limb ischemic postconditioning protects against neonatalhypoxic ischemic brain injury in rat pups by the opioid receptor/Akt pathway.Stroke 42, 439–444 (2011).14. Ren, C. et al. Limb remote ischemic postconditioning protects against focalischemia in rats. Brain Res. 1288, 88–94 (2009).15. Ezzati, M. et al. Immediate remote ischemic postconditioning after hypoxiaischemia in piglets protects cerebral white matter but not grey matter. J. Cereb.Blood Flow. Metab. 36, 1396–1411 (2016).16. Kyng, K. J. Short-term outcomes of remote ischemic postconditioning 1 h afterperinatal hypoxia-ischemia in term piglets. Pediatr. Res. 89, 150–156 (2021).17. Andelius, T. C. K. et al. No added neuroprotective effect of remote ischemicpostconditioning and therapeutic hypothermia after mild hypoxia-ischemia in apiglet model. Front. Pediatr. 26, 299 (2020).18. Chen, H. S. et al. RICAMIS investigators. effect of remote ischemic conditioning vsusual care on neurologic function in patients with acute moderate ischemicstroke: The RICAMIS randomized clinical trial. JAMA 328, 627–636 (2022).19. Zhao, W. et al. Remote ischaemic conditioning for preventing and treatingischaemic stroke. Cochrane Database Syst. Rev. 7, CD012503 (2018).20. England, T. J. et al. RECAST (Remote Ischemic Conditioning After Stroke Trial): Apilot randomized placebo controlled Phase II trial in acute ischemic stroke. Stroke48, 1412–1415 (2017).21. Hodoodi, F. et al. The effect of head cooling and remote ischemic conditioningon patients with traumatic brain injury. iScience 24, 102472 (2021).22. Ganji, N. et al. Remote ischemic conditioning in necrotizing enterocolitis. Semin.Pediatr. Surg. 32, 151312 (2023).23. Zozaya, C. et al. Remote ischaemic conditioning in necrotising enterocolitis: aphase I feasibility and safety study. Arch. Dis. Child Fetal Neonatal Ed. 108, 69–76(2023).24. Fleiss, B. & Gressens, P. Tertiary mechanisms of brain damage: a new hope fortreatment of cerebral palsy? Lancet Neurol. 11, 556–566 (2016).25. Li, Q. et al. Remote ischemic conditioning with medical management or reper-fusion therapy for acute ischemic stroke: a systematic review and meta-analysis.Neurology 102, e207983 (2024).26. Kharbanda, R. K. et al. Transient limb ischemia induces remote ischemic pre-conditioning in vivo. Circulation 106, 2881–2883 (2002).ACKNOWLEDGEMENTSThis research received a proportion of funding from the United Kingdom Departmentof Health’s National Institute for Health Research Biomedical Research CentresFunding Scheme (NJR is a BRC4 principal investigator within the TranslationalNeuroscience Theme). NJR is supported by the Gates Foundation (INV‐002322, UKRI(MR/X030067/1) and the Wellbeing of Women (RG2222). Derek Hausenloy issupported by the Duke-NUS Signature Research Programme funded by the Ministryof Health, Singapore Ministry of Health’s National Medical Research Council under itsSingapore Translational Research Investigator Award (MOH-STaR21jun-0003), CentreGrant scheme (NMRC CG21APR1006), and Collaborative Centre Grant scheme (NMRC/CG21APRC006).COMPETING INTERESTSThe authors declare no competing interests.ADDITIONAL INFORMATIONCorrespondence and requests for materials should be addressed toNicola J. Robertson.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons licence, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons licence, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons licence and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2025N.J. Robertson et al.3Pediatric Research

Remote ischaemic post conditioning in NE: A feasible and simple paradigm for self-protection in the brain?

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Remote ischaemic post conditioning in NE: A feasible and simple paradigm for self-protection in the brain?

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