Exposure to 16\u2009h of normobaric hypoxia induces ionic edema in the healthy brain

Armin Biller,Martin Bendszus,Philipp Guericke,Kai Schommer,Heimo Mairbäurl,Peter Bärtsch,Armin M Nagel,Andreas Heckel,Sabine Heiland,Stephanie Badde

doi:10.1038/s41467-021-26116-y

Abstract

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktrans as a marker of blood–brain–barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.

Highlights

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop
Prolonged exposure to hypoxic conditions can lead to the formation of cerebral edema
To comprehensively assess the nature of these edemas, we exposed healthy humans to 16 h of normobaric hypoxia created by simulating a sudden ascent to a high altitude of 4500 m and measured the effects on the brain using sodium, dynamic contrast enhanced (DCE), and proton magnetic resonance imaging (MRI) techniques

Summary

Introduction

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI This dual approach allowed us to directly measure key factors in the development of hypoxiainduced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktrans as a marker of blood–brain–barrier integrity. Further damage of the endothelium results in growing permeability pores and the passage of erythrocytes into the brain tissue, i.e., hemorrhagic transformation This cascadic model of edema formation (Fig. 1) explains the heterogenic outcomes of previous canonical, proton MRI studies investigating the impact of normobaric hypoxia on the healthy brain (Table 1). The conjoined analysis of ATS and FAS signals allows for a differentiation between brain areas with impaired Na+/K+-ATPase compatible with intracellular sodium accumulation, such as in focal ischemia[21,22,23], high-grade brain tumors[18,19,24,25,26], or acute multiple sclerosis lesions[27,28,29,30], and areas with extracellular sodium accumulation, such as in perifocal edema or chronic inflammatory lesions

Methods

Results

Conclusion