Effect of Cyclooxygenase Inhibitor on Hypoxia Stimulated Cerebral Blood Flow Using Arterial Spin Labeling Magnetic Resonance

Abstract

IntroductionThe purpose of this study was twofold: 1) to determine microvascular cerebral blood flow (CBF) during hypoxia and 2) to investigate the effect of Ketorolac, a cyclooxygenase (COX) inhibitor, on hypoxia stimulated CBF. Acute exposure to hypoxic conditions leads to an increase in CBF, which may be regionally specific. Studies investigating the effect of hypoxia on CBF have utilized varying gradations and durations of hypoxia and different measuring techniques (transcranial doppler ultrasound or magnetic resonance imaging (MRI)). COX has been shown to significantly contribute to CBF at rest, however during hypoxia research has shown conflicting data on COX contribution to hypoxic CBF. Utilizing arterial spin labeling (ASL), an MRI technique that provides microvascular global and regional perfusion, during hypoxia stimulated CBF and the role of COX. We hypothesized hypoxia will increase CBF non‐uniformly, and COX inhibition with Ketorolac will reduce hypoxic dilation in some, but not all brain regions.Methods6 healthy young adults subjects (24 ± 3 years, 22.4 ± 0.7 BMI, 4 male) were included in this analysis using an institutional review board (IRB)‐approved protocol. Subjects completed an ASL MRI scans (5.5 min each) under the 3 distinct conditions: normoxia, hypoxia, and hypoxia + ketorolac drug infusion. The first ASL scan occurred while the subject breathed ambient air (baseline). Isocapnic hypoxia was then induced by breathing reduced O2 (9‐13%) to reduce arterial saturation to 80‐85% for steady state hypoxia followed by the first hypoxia ASL scan. While hypoxia was maintained, Ketorolac was infused at a rate of 0.495 mg/kg over 3 minutes (average dose 33.9 ± 2.8 mg), the third ASL scan was then completed (hypoxia+ketorolac). ASL analysis included smoothing grey matter, co‐registering and normalizing raw data, brain masking and region of interest processing. Statistics were determined using a Two‐Way Repeated Measures ANOVA with Tukey’s post‐hoc analysis.ResultsData are mean ± SD. SpO2 (98 ± 1%, 82 ± 2%, 82 ± 1%) and ETCO2 (36 ± 1mmHg, 35 ± 2mmHg, 34 ± 2) at baseline, hypoxia, and hypoxia+ketorolac, respectively. Baseline Global CBF (58 ± 15 ml/100g‐1/min‐1) was not significantly different from hypoxia (61 ± 14 ml/100g‐1/min‐1) (p=0.47). Regionally, CBF between baseline and hypoxia were not different in the right/left temporal, occipital, parietal, or frontal lobes (R/L: p=0.47/p=0.98, p=0.59/p=0.49, p=0.46/p=0.63, and p=0.18/0.19, respectively). Ketorolac did not change global CBF during hypoxia (60 ± 17 ml/100g‐1/min‐1) (p=0.96). Regional CBF during hypoxia and hypoxia+ketorolac was not changed in the right/left temporal, occipital, parietal, or frontal lobes (R/L: p=0.96/0.91, p=0.57/0.88, p=0.86/0.99, and p=0.38/0.35, respectively).DiscussionContrary to our hypothesis CBF did not change globally or regionally with hypoxia stimulation. Furthermore, COX inhibition via Ketorolac did not change CBF during hypoxia in any region. This finding corroborates previous studies in animals and macrovascular flow in humans that COX inhibitor Ketorolac acts differently in the brain compared to Indomethacin, despite similar pharmacology. In conclusion, acute hypoxia exposure with Ketorolac did not alter microvascular CBF.