Hypoxic–ischemic encephalopathy (HIE) is a major contributor to death and disability worldwide. Remote ischemic postconditioning (RIPC) may offer neuroprotection but has only been tested in preclinical models. Various preclinical models with different assessments of outcomes complicate interpretation. The objective of this systematic review was to determine the neuroprotective effect of RIPC in animal models of HIE.
The protocol was preregistered at The International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020205944). Literature was searched in PubMed, Embase, and Web of Science (April 2020). A formal meta-analysis was impossible due to heterogeneity and a descriptive synthesis was performed.
Thirty-two papers were screened, and five papers were included in the analysis. These included three piglet studies and two rat studies. A broad range of outcome measures was assessed, with inconsistent results. RIPC improved brain lactate/N-acetylaspartate ratios in two piglet studies, suggesting a limited metabolic effect, while most other outcomes assessed were equally likely to improve or not.
There is a lack of evidence to evaluate the neuroprotective effect of RIPC in HIE. Additional studies should aim to standardize methodology and outcome acquisition focusing on clinically relevant outcomes. Future studies should address the optimal timing and duration of RIPC and the combination with therapeutic hypothermia.
This systematic review summarizes five preclinical studies that reported inconsistent effects of RIPC as a neuroprotective intervention after hypoxia–ischemia.
The heterogeneity of hypoxia–ischemia animal models employed, mode of postconditioning, and diverse outcomes assessed at varying times means the key message is that no clear conclusions on effect can be drawn.
This review highlights the need for future studies to be designed with standardized methodology and common clinically relevant outcomes in models with documented translatability to the human condition.
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Douglas-Escobar, M. & Weiss, M. D. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 169, 397–403 (2015).
Adstamongkonkul, D. & Hess, D. C. Ischemic conditioning and neonatal hypoxic ischemic encephalopathy: a literature review. Cond. Med. 1, 9–16 (2017).
Loukogeorgakis, S. P. et al. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a KATP channel-dependent mechanism. Circulation 116, 1386–1395 (2007).
Zhao, J. J. et al. Remote ischemic postconditioning for ischemic stroke: a systematic review and meta-analysis of randomized controlled trials. Chin. Med. J. 131, 956–965 (2018).
Ritskes-Hoitinga, M. et al. Systematic reviews of preclinical animal studies can make significant contributions to health care and more transparent translational medicine. Cochrane Database Syst. Rev. ED000078 (2014). https://doi.org/10.1002/14651858.ED000078.
CAMARADES. Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies. http://www.camarades.info/ (2013).
P-269 SYRCLE. Systematic Review Centre for Laboratory animal Experimentation 269. https://www.syrcle.network (2012).
Booth, A. The pros and pros of registration on PROSPERO. BJOG 119, 904–905 (2012).
Shamseer, L. et al. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: elaboration and explanation. BMJ 349, g7647 (2015).
Macleod, M. R., O’Collins, T., Howells, D. W. & Donnan, G. A. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35, 1203–1208 (2004).
Hooijmans, C. R. et al. SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Methodol. 14, 43 (2014).
Drunalini Perera, P. N. et al. Delayed remote ischemic postconditioning improves long term sensory motor deficits in a neonatal hypoxic ischemic rat model. PLoS ONE 9, e90258 (2014).
Zhou, Y. et al. Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/akt pathway. Stroke 42, 439–444 (2011).
Kyng, K. J. et al. Short-term outcomes of remote ischemic postconditioning 1 h after perinatal hypoxia–ischemia in term piglets. Pediatr. Res. 89, 150–156 (2021).
Ezzati, M. et al. Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter. J. Cereb. Blood Flow. Metab. 36, 1396–1411 (2016).
Rocha-Ferreira, E. et al. Immediate remote ischemic postconditioning reduces brain nitrotyrosine formation in a Piglet Asphyxia Model. Oxid. Med. Cell Longev. 2016, 5763743 (2016).
Lally, P. J. et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 18, 35–45 (2019).
Peden, C. J. et al. Proton spectroscopy of the neonatal brain following hypoxic-ischaemic injury. Dev. Med. Child Neurol. 35, 502–510 (1993).
Cheong, J. L. Y. et al. Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: metabolite peak-area ratios, relaxation times, and absolute concentrations. Am. J. Neuroradiol. 27, 1546–1554 (2006).
Park, R. Lactic acidosis. West J. Med. 133, 418–424 (1980).
Hagberg, H., Mallard, C., Rousset, C. I. & Thornton, C. Mitochondria: hub of injury responses in the developing brain. Lancet Neurol. 13, 217–232 (2014).
Gardai, S. J. et al. Phosphorylation of Bax ser184 by Akt regulates its activity and apoptosis in neutrophils. J. Biol. Chem. 279, 21085–21095 (2004).
Leker, R. R. et al. Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 909, 1–7 (2001).
Erkenstam, N. H. et al. Temporal characterization of microglia/macrophage phenotypes in a mouse model of neonatal hypoxic-ischemic brain injury. Front. Cell Neurosci. 10, 286 (2016).
Davidson, J. O. et al. Perinatal brain injury: mechanisms and therapeutic approaches. Front. Biosci. 23, 2204–2226 (2018).
Bart van der Worp, H. et al. Can animal models of disease reliably inform human studies? PLoS Med. 7, 1–8 (2010).
Steinmeyer, K. et al. Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease. J. Biol. Chem. 270, 31172–31177 (1995).
Button, K. S. et al. Power failure: Why small sample size undermines the reliability of neuroscience. Nat. Rev. Neurosci. 14, 365–376 (2013).
Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev. 2013, CD003311 (2013).
Galinsky, R. et al. In the era of therapeutic hypothermia, how well do studies of perinatal neuroprotection control temperature? Dev. Neurosci. 39, 7–22 (2017).
Clough, G. Environmental effects on animals used in biomedical research. Biol. Rev. 57, 487–523 (1982).
Marrino, P., Gavish, D., Shafrir, E. & Eisenberg, S. Diurnal variations of plasma lipids, tissue and plasma lipoprotein lipase, and VLDL secretion rates in the rat. A model for studies of VLDL metabolism. Biochim. Biophys. Acta 920, 277–284 (1987).
Chen, G., Kamat, P. K., Ahmad, A. S. & Doré, S. Distinctive effect of anesthetics on the effect of limb remote ischemic postconditioning following ischemic stroke. PLoS ONE 15, e0227624 (2020).
du Sert, N. P. et al. The arrive guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 18, e3000410 (2020).
Kilkenny, C. et al. Improving bioscience research reporting: the arrive guidelines for reporting animal research. PLoS Biol. 8, 8–9 (2010).
Andelius, T. C. K. et al. No Added neuroprotective effect of remote ischemic postconditioning and therapeutic hypothermia after mild hypoxia-ischemia in a piglet model. Front. Pediatr. 8, 299 (2020).
Yellon, D. M. & Downey, J. M. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol. Rev. 83, 1113–1151 (2003).
Wei, M. et al. Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ. Res. 108, 1220–1225 (2011).
Fisher, M. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30, 2752–2758 (1999).
This research was funded by Ludvig and Sara Elsass Foundation (grant number 20-3-0296) and The Health Research Foundation of Central Denmark Region.
The authors declare no competing interests.
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Andelius, T.C.K., Henriksen, T.B., Kousholt, B.S. et al. Remote ischemic postconditioning for neuroprotection after newborn hypoxia–ischemia: systematic review of preclinical studies. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01656-7