Efficacy and Safety Study of Urapidil Alone or With Esmolol in Treating Acute Hypertensive Intracerebral Hemorrhage

Hypertensive intracerebral hemorrhage (HICH) is a prevalent and severe condition that poses significant challenges to the medical community due to its harmful nature and complexity. Over the past few decades, there has been considerable controversy surrounding blood pressure management strategies for patients with acute HICH. Both hypertension and hypotension following cerebral hemorrhage are associated with adverse outcomes. Multiple trials aimed at reducing blood pressure in patients with acute cerebral hemorrhage have been conducted, and among patients recruited within six hours of symptom onset, blood pressure reduction has been linked to decreased hematoma expansion. Current international guidelines from the European Stroke Organization, the American Heart Association (AHA)/American Stroke Association, and the Canadian Stroke Best Practice Recommendations support the prompt reduction of systolic blood pressure to 140 mmHg after symptom onset, aiming to maintain systolic blood pressure between 130 and 150 mmHg. However, for certain patients, such as those with extremely high blood pressure after ICH (systolic blood pressure >220 mmHg), a more individualized approach is necessary. Notably, patients with very high blood pressure (systolic blood pressure >220 mmHg) were not included in these trials, and reducing systolic blood pressure to 140 mmHg in this population may be harmful, associated with higher rates of neurological deterioration and adverse renal events.

Elevated blood pressure (BP) is common in patients with acute spontaneous intracerebral hemorrhage (ICH) and is closely related to hematoma growth, which is a crucial independent predictor of clinical deterioration and outcomes in ICH patients. Previous studies have shown that hematoma growth primarily occurs within the first six hours after spontaneous cerebral hemorrhage. Consequently, early blood pressure reduction may be beneficial in preventing hematoma growth. Research indicates that ICH patients who achieve target blood pressure more quickly are less likely to experience hematoma growth. Specifically, patients who reach a target systolic blood pressure (SBP) of <140 mmHg within the first hour after randomization exhibit a lower absolute hematoma growth rate. Studies have supported the benefit of shortening the time to achieve target blood pressure in ICH patients, corroborating these findings. Hematoma growth is primarily attributed to ongoing bleeding and secondary vascular rupture, occurring predominantly within the first six hours after ICH onset, particularly during the initial 2-3 hours, with a gradual decline in frequency over time.

Changes in the autonomic nervous system (ANS) have been previously observed in acute stroke patients, characterized by impaired cardiovascular regulation and altered balance between sympathetic and parasympathetic nerves. Clinically significantly, autonomic dysfunction is associated with poor prognosis, increased mortality, or sudden death after stroke. Variations in heart rate variability (HRV) and baroreceptor sensitivity (BRS) have traditionally been considered surrogate markers of cardiovascular ANS modulation. Previous studies on HRV in acute brain injury have primarily focused on ischemic cerebral infarction or traumatic brain injury (TBI). In both TBI and ischemic cerebral infarction, HRV parameters have shown independent associations with outcomes.

Urapidil (URA) is a selective α1-adrenoceptor antagonist that also acts as a central 5-HT1A receptor agonist, exerting both peripheral and central hypotensive effects. The hypotensive effect of URA is dose-dependent and may vary among individuals. URA demonstrates a self-limiting hypotensive effect, even at high doses, without causing severe hypotension. It reduces cardiac preload and afterload, decreases myocardial oxygen consumption, and increases cardiac output without causing reflex tachycardia or affecting heart rate. Additionally, URA does not increase intracranial pressure, does not impair hemodynamics in the middle cerebral artery, and is conducive to maintaining cerebral perfusion pressure. Furthermore, URA enhances renal blood flow, reduces renal vascular resistance, does not increase shunt fraction, and does not decrease arterial oxygen partial pressure.

Esmolol is an ultra-short-acting, highly selective β1-blocker that competitively antagonizes β1 receptors in myocardial cells. It exerts its pharmacological effects by blocking the activity of adrenaline and noradrenaline. At high doses, it may also block β2 receptors in airway and vascular smooth muscle. At therapeutic doses, esmolol has no intrinsic sympathomimetic activity or membrane-stabilizing effects. When administered intravenously, it takes effect within 60 seconds and its pharmacological effects disappear within 10 to 30 minutes after infusion cessation. Electrophysiological studies suggest that esmolol exhibits typical β1-blocker effects, including reduced heart rate, prolonged sinus cycle length, prolonged sinus node recovery time, prolonged AH interval and antegrade Wenckebach period, slowed conduction in atrial and ventricular myocardium and cardiac conduction system, and prolonged refractoriness. By blocking sympathetic excitation, esmolol lowers the threshold for ventricular fibrillation (VF).

Patients with acute HICH often experience increased heart rate and uncontrolled blood pressure. Previous studies have shown that the time taken to normalize blood pressure and heart rate variability are correlated with adverse outcomes in patients. The present study aims to evaluate the effectiveness of urapidil alone and in combination with esmolol in reducing blood pressure and controlling heart rate in patients with acute.