Secondary mechanisms of injury and viable pathophysiological targets in intracerebral hemorrhage

You'll want this solved before you have this type of stroke. So ask your doctor and hospital EXACTLY WHAT RESEARCH THEY ARE INITIATING TO SOLVE THIS. No research, have the board of directors fired. 

Secondary mechanisms of injury and viable pathophysiological targets in intracerebral hemorrhage

 

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Wendy Bautista, P. David Adelson, Nathan Bicher, ...

First Published October 13, 2021 Review Article 

https://doi.org/10.1177/17562864211049208

Article information

Abstract

Intracerebral hemorrhage (ICH) can be divided into a primary and secondary phase. In the primary phase, hematoma volume is evaluated and therapies are focused on reducing hematoma expansion. In the secondary, neuroprotective phase, complex systemic inflammatory cascades, direct cellular toxicity, and blood-brain barrier disruption can result in worsening perihematomal edema that can adversely affect functional outcome. To date, all major randomized phase 3 trials for ICH have targeted primary phase hematoma volume and incorporated clot evacuation, intensive blood pressure control, and hemostasis. Reasons for this lack of clinical efficacy in the major ICH trials may be due to the lack of therapeutics involving mitigation of secondary injury and inflexible trial design that favors unilateral mechanisms in a complex pathophysiology. Potential pathophysiological targets for attenuating secondary injury are highlighted in this review and include therapies increasing calcium, antagonizing microglial activation, maintaining macrophage M1 versus M2 balance by decreasing M1 signaling, aquaporin inhibition, NKCCl inhibition, endothelin receptor inhibition, Sur1-TRPM4 inhibition, matrix metalloproteinase inhibition, and sphingosine-1-phosphate receptor modulation. Future clinical trials in ICH focusing on secondary phase injury and, potentially implementing adaptive trial design approaches with multifocal targets, may improve insight into these mechanisms and provide potential therapies that may improve survival and functional outcome.

Keywords

intracerebral hemorrhage, neuroprotection, perihematomal edema, secondary injury, vasogenic edema

Introduction

Spontaneous intracerebral hemorrhage (ICH) is one of the most common causes of death and disability in the USA, with over 795,000 new strokes every year of which 10% are ICH (incidence of 24.6 per 100,000 person-years).^1,2 However, while the incidence remains steady, ICH boasts the highest mortality with rates ranging between 53% and 59%^1,3,4 and the highest comorbidities in patients 50–80 years old.¹

The primary phase in ICH management, calculating initial hematoma volume and rate of expansion, has been aggressively targeted in large multicenter trials over the last 15 years (Table 1).^5–11 Despite the number of major clinical trials, all of the novel therapeutic strategies targeting primary mechanisms from these clinical trials have been unsuccessful in demonstrating improved functional outcome, suggesting that secondary mechanisms of injury after ICH may represent a complementary and essential pathophysiological target.

Table 1. Summary of clinical trials targeting primary phase hematoma volume and expansion.

Table 1. Summary of clinical trials targeting primary phase hematoma volume and expansion.

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In this review, we summarize pathophysiological mechanisms critical in wound repair after ICH and current evidence from important clinical trials that suggest viable therapeutic targets for attenuating secondary injury in patients with ICH. We also propose a new paradigm to establish novel strategies and targets for future ICH therapy clinical trials that can specifically target secondary mechanisms of injury. The lack of efficacy in therapies targeting primary mechanisms in ICH, emphasizes the need for better prospective clinical trials that both target and provide quick therapies to mitigate secondary mechanisms of injury.