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  • Review Article
  • Published:

Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema

Nature Reviews Neurology volume 11, pages 111–122 (2015)Cite this article

Subjects

Key Points

  • Secondary injury following intracerebral haemorrhage (ICH) is caused by perihaemorrhagic inflammation, toxic products of blood breakdown, and perihaematomal oedema (PHO)

  • Secondary injury contributes to neurological deterioration over an extended period of hours to days and, therefore, offers a long therapeutic window

  • PHO forms in three stages in accordance with Starling's principle: stage 1 is characterized by ionic oedema, and stages 2 and 3 by progressive vasogenic oedema

  • PHO is a pathophysiological marker of secondary injury that could provide a useful surrogate end point for testing novel neuroprotective agents

  • PHO might also be clinically relevant, as it augments the mass effect of haemorrhage; further studies could identify subgroups of patients who would benefit from therapies that ameliorate PHO

  • Combination treatment regimens that target different stages of PHO formation might be most effective to reduce swelling

Abstract

Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury.

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Figure 1: A modification of Starling's equation that includes separate filtration coefficients for the hydrostatic and osmotic forces.
Figure 2: Hypothetical model of NKCC1 and SUR1–TRPM4 involvement in PHO.
Figure 3: Expression of SUR1–TRPM4 in perihaematomal tissues following primary spontaneous ICH.
Figure 4: Intracerebral haemorrhage and PHO as seen in a CT scan performed at hospital admission.

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Acknowledgements

S.U. is supported by the Leon Rosenberg, MD Medical Student Research Fund in Genetics (Yale University School of Medicine) and a 2014 Student Scholarship in Cerebrovascular Disease and Stroke (American Heart Association Stroke Council). L.A.B. is supported by the National Institute of Neurological Disorders and Stroke (NINDS; K12-NS049453). J.M.S. is supported by grants from the Department of Veterans Affairs (Baltimore; BX001629), the NINDS (NS060801, NS061808), and the National Heart, Lung and Blood Institute (HL082517).

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Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Sebastian Urday, Lauren A. Beslow & Kevin N. Sheth

  2. Department of Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Alexander O. Vortmeyer

  3. Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    W. Taylor Kimberly & Jonathan Rosand

  4. Department of Neurology, Beth Israel Deaconess Medical Centre, 330 Brookline Avenue, Boston, 02215, MA, USA

    Magdy H. Selim

  5. Department of Neurosurgery, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, 21201-1559, MD, USA

    J. Marc Simard

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  1. Sebastian Urday
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  2. W. Taylor Kimberly
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  3. Lauren A. Beslow
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  4. Alexander O. Vortmeyer
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  5. Magdy H. Selim
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  6. Jonathan Rosand
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  7. J. Marc Simard
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  8. Kevin N. Sheth
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Contributions

S.U. and K.N.S. originated the overall concept for this Review. All authors contributed to several drafts of the article and provided important intellectual exchanges during formulation of key concepts. S.U., J.M.S. and K.N.S. contributed to every draft and supplied figures. A.O.V. was responsible for procuring autopsy specimens, and J.M.S. was responsible for SUR1 detection in intracerebral haemorrhage tissue shown in Figure 3.

Corresponding author

Correspondence to Kevin N. Sheth.

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Competing interests

W.T.K., and L.A.B. and K.N.S. are investigators in GAMES-RP, a phase II study of an investigational compound aimed at preventing swelling after large stroke. J.M.S. holds a US patent (7,285,574, Methods for treating neural cell swelling). The other authors declare no competing interests.

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Urday, S., Kimberly, W., Beslow, L. et al. Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema. Nat Rev Neurol 11, 111–122 (2015). https://doi.org/10.1038/nrneurol.2014.264

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