Low oxygen in inspired air causes severe cerebrocortical hypoxia and cell death in the cerebral cortex of awake rats

Abstract

Type 1 respiratory failure (T1RF) is associated with secondary acute brain injury (sABI). The underlying mechanisms of sABI could include injury to brain cells mediated either by hypoxia or by lung injury-triggered inflammation. To elucidate to what extent T1RF causes hypoxia and a consequent hypoxic injury in the brain in the absence of lung injury, we exposed healthy, conscious Sprague-Dawley rats to 48 h long low partial pressure of O₂ in inspired air (PiO₂) (7.5-8 % O₂ in N₂, CO₂ < 0.5 %, normal barometric pressure) and measured the partial pressure of oxygen in the premotor cortex (PtO₂), cerebral blood flow (CBF), lactate concentrations, and cell death. Low PiO₂ significantly affected PtO₂, which was 52.3 (SD 2.1) mmHg when PiO₂ was normal but declined to 6.4 (SD 3.8) mmHg when PiO₂ was low for 1 h. This was accompanied by increased lactate concentrations in plasma, CSF, and premotor cortex. Low PiO₂ elevated the number of dead cells in the cerebral cortex from 5.6 (SD 4.8) % (when PiO₂ was normal) to 20.5 (SD 4.1) % and 32.37 (SD 6.5) % after 24 h and 48 h exposure to low PiO₂, respectively. The Mann-Kendall test could not detect any monotonic increase or decrease in pial blood flow during the 48 h exposure to low PiO₂. In summary, our findings suggest that exposure to low PiO₂ caused a severe hypoxia in the cerebral cortex, which triggers a massive cell death. Since these conditions mimic T1RF, hypoxic injury could be an important underlying cause of T1RF-induced sABI.

Keywords: Cell death; Cerebral blood flow; Cerebral cortex; Hypoxia; Lactate; Type 1 respiratory failure.