Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination?

OBJECTIVES: Despite several advantages of the novel anticoagulant rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications. The purpose of this study was to analyze the effects of pre-injury treatment with rivaroxaban on patients with mild traumatic brain injury (TBI) and traumatic intracranial haemorrhage (tICH). METHODS: A total of 70 patients with tICH after mild TBI were included in this retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality. RESULTS: No significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C. CONCLUSIONS: Despite major limitations of retrospective design and small patient numbers, our results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH.

Brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury.

Cerebral ischemia is a well-recognized contributor to high morbidity and mortality after traumatic brain injury (TBI). Standard of care treatment aims to maintain a sufficient oxygen supply to the brain by avoiding increased intracranial pressure (ICP) and ensuring a sufficient cerebral perfusion pressure (CPP). Devices allowing direct assessment of brain tissue oxygenation have showed promising results in clinical studies, and their use was implemented in the Brain Trauma Foundation Guidelines for the treatment of TBI patients in 2007. Results of several studies suggest that a brain tissue oxygen-directed therapy guided by these monitors may contribute to reduced mortality and improved outcome of TBI patients. Whether increasing the oxygen supply to supraphysiological levels has beneficial or detrimental effects on TBI patients has been a matter of debate for decades. The results of trials of hyperbaric oxygenation (HBO) have failed to show a benefit, but renewed interest in normobaric hyperoxia (NBO) in the treatment of TBI patients has emerged in recent years. With the increased availability of advanced neuromonitoring devices such as brain tissue oxygen monitors, it was shown that some patients might benefit from this therapeutic approach. In this article, we review the pathophysiological rationale and technical modalities of brain tissue oxygen monitors, as well as its use in studies of brain tissue oxygen-directed therapy. Furthermore, we analyze hyperoxia as a treatment option in TBI patients, summarize the results of clinical trials, and give insights into the recent findings of hyperoxic effects on cerebral metabolism after TBI.

Delayed hyperbaric oxygenation is more effective than early prolonged normobaric hyperoxia in experimental focal cerebral ischemia.

Hyperbaric (HBO) and normobaric (NBO) oxygen therapy have been shown to be neuroprotective in focal cerebral ischemia. In previous comparative studies, NBO appeared to be less effective than HBO. However, the experimental protocols did not account for important advantages of NBO in the clinical setting such as earlier initiation and prolonged administration. Therefore, we compared the effects of early prolonged NBO to delayed HBO on infarct size and functional outcome. We also examined whether combining NBO and HBO is of additional benefit. Wistar rats underwent filament-induced middle cerebral artery occlusion (MCAO) for 150 min. Animals breathed either air, 100% O(2) at ambient pressure (NBO; initiated 30 min after MCAO) 100% O(2) at 3 atm absolute (HBO; initiated 90 min after MCAO), or a sequence of NBO and HBO. Infarct volumes and neurological outcome (Garcia score) were examined 7d after MCAO. HBO (174+/-65 mm(3)) significantly reduced mean infarct volume by 31% compared to air (251+/-59 mm(3)) and by 23% compared to NBO treated animals (225+/-63 mm(3)). In contrast, NBO failed to decrease infarct volume significantly. Treatment with NBO+HBO (185+/-101 mm(3)) added no additional benefit to HBO alone. Neurological deficit was significantly smaller in HBO treated animals (Garcia score: 13.3+/-1.2) than in animals treated with air (12.1+/-1.4), but did not differ significantly from NBO (12.4+/-0.9) and NBO+HBO (12.8+/-1.1). In conclusion, HBO is a more effective therapy than NBO in transient experimental ischemia even when accounting for delayed treatment-onset of HBO. The combination of NBO and HBO results in no additional benefit.

Hyperbaric oxygen reduces basal lamina degradation after transient focal cerebral ischemia in rats.

Hyperbaric oxygen (HBO) has been shown to preserve the integrity of the blood-brain barrier after cerebral ischemia. However, the underlying molecular mechanisms are currently unknown. We examined the effect of HBO on postischemic expression of the basal laminar component laminin-5 and on plasma matrix metalloproteinase-9 (MMP) levels. Wistar rats underwent occlusion of the middle cerebral artery (MCAO) for 2 h. With a delay of 45 min after filament introduction, animals breathed either 100% O2 at 1.0 atmosphere absolute (ata; NBO) or at 3.0 ata (HBO) for 1 h in an HBO chamber. Laminin-5 expression was quantified on immunohistochemical sections after 24 h of reperfusion. Plasma MMP-9 levels were measured using gelatin zymography before MCAO as well as 0, 6 and 24 h after reperfusion. Immunohistochemistry 24 h after ischemia revealed a decrease of vascular laminin-5 staining in the ischemic striatum to 43 +/- 26% of the contralateral hemisphere in the NBO group which was significantly attenuated to 73 +/- 31% in the HBO group. Densitometric analysis of zymography bands yielded significantly larger plasma MMP-9 levels in the NBO group compared to the HBO group 24 h after ischemia. In conclusion, HBO therapy attenuates ischemic degradation of cerebral microvascular laminin-5 and blocks postischemic plasma MMP-9 upregulation.