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Remote ischemic postconditioning for neuroprotection after newborn hypoxia–ischemia: systematic review of preclinical studies

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Impact

  • 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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Fig. 1: PRISMA flow chart for screening and selection of included studies.

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Acknowledgements

This research was funded by Ludvig and Sara Elsass Foundation (grant number 20-3-0296) and The Health Research Foundation of Central Denmark Region.

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Conceptualization, T.C.K.A., B.S.K., and K.J.K.; writing the original draft, T.C.K.A., T.B.H., B.S.K., and K.J.K.; writing-review and editing, T.C.K.A., T.B.H., B.S.K., and K.J.K. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Kasper J. Kyng.

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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

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