Abstract
Background and Purpose: The morbidity and early mortality associated with stroke is largely attributable to cerebral edema and elevated intracranial pressure (ICP). Existing pharmacotherapies do not target the underlying pathophysiology and are often ineffective in sustainably lowering ICP, whilst decompressive craniectomy (DC) surgery is life-saving yet with surgical/peri-operative risk and increased morbidity in the elderly. Accordingly, there is an urgent need for therapies that directly target the mechanisms of edema genesis. Neurogenic inflammation, mediated by substance P (SP) binding to the tachykinin NK1 receptor (NK1-r), is associated with blood-brain barrier (BBB) disruption, cerebral edema and poor outcome post-stroke. NK1-r antagonist treatment ameliorates BBB dysfunction and cerebral edema in rodent stroke models. However, treatment has not been investigated in a large animal model, an important step toward clinical translation. Consequently, the current study compared the efficacy of NK1-r antagonist treatment to DC surgery in reducing ICP post-stroke in a clinically relevant ovine model.Methods: Anesthetized female Merino sheep (65 ± 6 kg, 18–24 months) underwent sham surgery (n = 4) or permanent middle cerebral artery occlusion (n = 22). Stroke animals were randomized into one of 5 treatments: 1×NK1 bolus (4 h), 2×NK1 bolus (4 h;9 h), 3×NK1 bolus (4 h;9 h;14 h), DC surgery (performed at 4 h) or saline vehicle. ICP, blood pressure and blood gasses were monitored for 24 h post-stroke. At 24 h post-stroke anesthetized animals underwent MRI followed by perfusion and brains removed and processed for histological assessment.Results: 2×NK1, 3×NK1 administration or DC surgery significantly (p < 0.05) reduced ICP compared to vehicle. 1×NK1 was ineffective in sustainably lowering ICP. On MRI, midline shift and cerebral edema were more marked in vehicles compared to NK1-r treatment groups.Conclusion: Two or three boluses of NK1-r antagonist treatment reduced ICP comparable to DC surgery, suggesting it may provide a novel alternative to invasive surgery for the management of elevated ICP.
Highlights
Elevated intracranial pressure (ICP) arising as a result of malignant cerebral edema is the leading cause of death in the first week following stroke (Hacke et al, 1996)
Despite the clear treatment effect of blocking the NK1 receptor (NK1-r) to reduce ICP in this study, we did not observe a significant increase in perivascular substance P (SP) immunoreactivity within the infarcted territory in any of the treatment groups following stroke
One dose of the NK1-r antagonist, was insufficient to produce a treatment effect with pressures averaging 35 mmHg. These findings suggest that multiple boluses of the NK1-r antagonist is a potentially viable therapeutic strategy to reduce elevated ICP following stroke, with the ability to bring about a clinically meaningful and sustainable reduction in pressure comparable to that observed in surviving patients (Hacke et al, 1996)
Summary
Elevated intracranial pressure (ICP) arising as a result of malignant cerebral edema is the leading cause of death in the first week following stroke (Hacke et al, 1996). In selected patients with malignant middle cerebral artery (MCA) territory infarction, surgical intervention with decompressive craniectomy (DC) may be required This procedure rapidly alleviates pressure by removing a large portion of the skull and opening the dura overlying the brain, thereby providing space for the edematous brain to swell freely until cerebral edema resolves, typically beyond the first week following stroke (Xiao-feng et al, 2005). This procedure reduces compression on cerebral structures and the risk of life-threatening tonsillar herniation, it is associated with increased morbidity in those aged greater than 60 years, the patient population in which stroke is most prevalent (Jüttler et al, 2007; Das et al, 2019). The current study compared the efficacy of NK1-r antagonist treatment to DC surgery in reducing ICP post-stroke in a clinically relevant ovine model
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