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  • Review Article
  • Published:

Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke

Nature Reviews Neurology volume 14, pages 325–337 (2018)Cite this article

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An Author Correction to this article was published on 11 February 2019

This article has been updated

Abstract

After ischaemic stroke, brain damage can be curtailed by rescuing the ‘ischaemic penumbra’ — that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Current evidence-based treatments involve restoration of blood flow so as to salvage the penumbra before it evolves into irreversibly damaged tissue, termed the ‘core’. Intravenous thrombolysis (IVT) can salvage the penumbra if given within 4.5 h after stroke onset; however, the early recanalization rate is only ~30%. Direct removal of the occluding clot by mechanical thrombectomy considerably improves outcomes over IVT alone, but despite early recanalization in > 80% of cases, ~50% of patients who receive this treatment do not enjoy functional independence, usually because the core is already too large at the time of recanalization. Novel therapies aiming to ‘freeze’ the penumbra — that is, prevent core growth until recanalization is complete — hold potential as adjuncts to mechanical thrombectomy. This Review focuses on nonpharmacological approaches that aim to restore the physiological balance between oxygen delivery to and oxygen demand of the penumbra. Particular emphasis is placed on normobaric oxygen therapy, hypothermia and sensory stimulation. Preclinical evidence and early pilot clinical trials are critically reviewed, and future directions, including clinical translation and trial design issues, are discussed.

Key points

  • The extent of brain damage following an ischaemic stroke can be limited by rapidly rescuing the ‘ischaemic penumbra’ — that is, the severely ischaemic, at-risk but not yet infarcted tissue.

  • Intravenous thrombolysis, which was licensed for clinical use in 1996, can salvage the penumbra if administered early after stroke onset; however, the recanalization rate is low.

  • Endovascular thrombectomy increases the likelihood of penumbral salvage and considerably improves outcomes; however, around half of the patients who undergo successful thrombectomy do not achieve functional independence, mainly because the infarct is already too large at the time of recanalization.

  • Novel therapies that aim to ‘freeze the penumbra’ — that is, to prevent infarct growth until recanalization is complete — hold considerable potential as adjuncts to thrombectomy.

  • This article focuses on nonpharmacological approaches to freeze the penumbra, which directly target penumbral hypoxia, are mostly non-invasive and easy to administer, have few or no adverse effects and might be delivered before hospital admission.

  • Emphasis is placed on normobaric hyperoxia, hypothermia and sensory stimulation, but other potential approaches, including transcranial direct cortical stimulation, perconditioning, perfluorocarbons, aortic balloon occlusion and sphenopalatine ganglion stimulation, are also presented.

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Fig. 1: The ischaemic penumbra in humans.
Fig. 2: Effects of normobaric hyperoxia on infarct volume.

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Change history

  • 11 February 2019

    The originally published article contained an error in Table 1, whereby the RESCUE trial appeared on the “Transient descending aortic balloon occlusion (TAO)” line instead of the “Remote ischaemic perconditioning (RIPerC)” line. This has been corrected in the HTML and PDF versions of the manuscript.

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Acknowledgements

The author thanks M. Bruyère for typing the supplementary tables.

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  1. Department of Neurology, Hôpital Sainte-Anne, Université Paris 5, INSERM U894, Paris, France

    Jean-Claude Baron

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Review criteria

A PubMed search of original and review articles was performed using the following search terms: “normobaric hyperoxia and stroke” or “hyperoxia and stroke”; “hypothermia and stroke”; “sensory stimulation and stroke”; “transcranial direct cortical stimulation and stroke” or “tDCS and stroke”; “per-conditioning and stroke”; “perfluorocarbons and stroke”; “aortic balloon occlusion and stroke” or “aortic occlusion and stroke”; and “spheno-palatine ganglion stimulation and stroke”. The articles that were selected for this Review used middle cerebral artery occlusion as a stroke model, were published in the English-language peer-reviewed literature and were published between 1975 and 2017.

Supplementary information

Glossary

Clinical–core mismatch

A mismatch between clinical presentation and size of the core on imaging, such that the clinical deficit appears larger than would be expected from the core alone, indicating that a large penumbra is also present.

Hyperbaric oxygen

(HBO). Oxygen delivered at a pressure higher than atmospheric pressure.

Normobaric oxygen

(NBO). Oxygen delivered at atmospheric pressure.

Apparent diffusion coefficient

(ADC). MRI-based physiological variable expressing the diffusion coefficient of water molecules in brain tissue, which is restricted in acutely ischaemic tissue.

Leptomeningeal collaterals

Arteriolar channels that anatomically connect the distal field arteriolar branches of the anterior, middle and posterior cerebral arteries at the cortical surface.

Neurovascular coupling

(NVC). A physiological process whereby neuronal activity, which increases neuronal energy metabolism, leads to dilation of the neighbouring vascular tree, causing increased local perfusion and, hence, delivery of energetic nutrients.

Somatosensory evoked potentials

(SSEPs). Discrete electrical responses to somatosensory stimulation occurring in the specialized neurons of the somatosensory cortex and recordable using various techniques.

Intra-tree anastomoses

Vascular connections similar to leptomeningeal collaterals but occurring between arterioles belonging to the same vascular system (for example, the middle cerebral artery).

Circle of Willis

The vascular channels connecting the anterior and posterior circulation and the right and left hemisphere arterial systems, situated at the base of the brain and, when complete, forming a continuous circle of connecting arteries.

‘Drip-and-ship’ paradigm

An acute stroke referral pathway in which a thrombolytic agent such as tissue plasminogen activator is administered in a community stroke unit and the patient is immediately transferred to the nearest comprehensive stroke centre for mechanical thrombectomy.

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Baron, JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nat Rev Neurol 14, 325–337 (2018). https://doi.org/10.1038/s41582-018-0002-2

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