Table 7.

Clinical studies on potential therapeutic targets for PHE after ICH.

Potential targets	Authors	Drugs/reagents/treatments	Samples	Time points	Main findings	References
Dehydration therapy	Shoamanesh et al.	Hypertonic normal saline, mannitol, glycerin, fructose, and albumin	Multiple studies	Guidelines based on multiple studies in the acute phase of ICH	Currently, there is insufficient evidence for the routine or prophylactic use of hyperosmotic agents in ICH. Mannitol and 3% normal saline can be considered a temporizing measure to decrease ICP in patients with ICH with clinical signs of herniation before surgical intervention.	[3]
	Cook et al.	Different dehydrate agents	Multiple studies	Guidelines based on multiple studies in the acute phase of ICH	The use of corticosteroids to treat ICP in ICH can cause harm, has no proven benefits, and is therefore not recommended. There is a dire need for high-quality research to better inform clinicians about the best options for personalized care of patients with cerebral edema.	[221]
Blood pressure control	Leasure et al.	Nicardipine	One thousand patients with primary ICH less than 60 mL and elevated systolic BP (>180 mm Hg)	Within 4.5 hours of onset (target SBP 110–139 mm Hg within 2 hours) or standard (target SBP 140–179 mm Hg within 2 hours)	Decrease in 24-hour PHER in deep ICH. Higher PHER predicted a poor outcome in basal ganglia ICH but not all deep ICH.	[144]
	Zang et al.	Urapidil	121 patients	Within 6 hours	Reduction in rebleeding and PHE. Improvement in short-term quality of life. Early intensive antihypertensive treatment had no impact on mortality.	[225]
	Zhang et al.	Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers	635 patients	Preuse	Decrease in mortality, volume of perihematomal edema, and prevalence of ICH-associated pneumonia.	[226]
Hemostasis	Jiang et al.	NA	NA	NA	Studies on the efficacy of hematoma expansion are currently controversial. No study has investigated the impact of hemostasis on PHE after ICH.	[227]
	Selim et al.	Deferoxamine mesylate (DFO)	294 patients	DFO (32 mg/kg/day) or saline (placebo) was infused for 3 consecutive days within 24 hours after ICH	Although DFO treatment was safe, it did not change functional outcome on day 90 after ICH.	[231]
	Wei et al.	Deferoxamine mesylate (DFO)	294 patients	DFO (32 mg/kg/day) or saline (placebo) was infused for 3 consecutive days within 24 hours after ICH	In 114 patients with moderate volume of hematoma (10-30 mL), deferoxamine alleviated functional deficit on day 90 after ICH.	[232]
Immunotherapies	Fu et al.	Fingolimod	23 primary supratentorial ICH patients with a volume of hematoma of 5 to 30 mL	Oral administration of fingolimod in 72 hours 3 times	Reduction in PHE. Attenuation in neurologic deficits.	[233]
	Chang et al.	Minocycline	20 patients	Minocycline was administered intravenously once a day, five days in total	No changes in clinical and radiological results. Serum levels of MMP-9 on day 5 tended to be lower in the minocycline group.	[235]
	Fouda et al.	Minocycline	16 patients	Intravenous administration once followed by oral administration every 4 days	Did not influence inflammatory biomarkers, hematoma volume, or perihematomal edema.	[236]
Surgical management	Zuo et al.	Gross-total removal of the hematoma	176 patients with hypertensive basal ganglia hemorrhage	Within 3 hours	Decrease in the formation of perihematomal edema and secondary injury.	[237]
	Fung et al.	Decompressive craniectomy	25 patients	15 (4–69) hours	A noticeable increase in perihematomal edema.	[239]
	Okuda et al.	Craniotomy or stereotactic hematoma evacuation	16 patients	Within 24 hours of onset	Reduction of brain edema.	[238]
	Horowitz et al.	Minimally invasive surgery (MIS)	36 patients	Unavailable	Decrease in pericavity edema.	[241]
	Lian et al.	Minimally invasive surgery+rt-PA	43 patients	6-72 hours after the onset of ICH	MIS reduced PHE volume. rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and a low dose of rt-PA reduced 30-day mortality in patients with severe ICH.	[242]
	Xia et al.	Minimally invasive craniopuncture with the hard- or soft-channel	150 patients with hypertensive intracerebral hemorrhage	Within 24 hours of onset	Minimally invasive soft-channel craniopuncture is more effective in treating HICH in alleviating cerebral edema, inhibiting oxidative stress, and inflammatory response.	[243]
Other therapy	Naval et al.	Statins	125 ICH patients	Prior statin exposure	The mean relative perihematomal edema was significantly lower in patients taking statins at presentation than in patients without prior statin use.	[244]
	Sprugel et al.	Statins	1,275 ICH patients	Initiation of statins after ICH during the first days after ICH	The initiation of statins during the first days after ICH may increase PHE. However, statins should be initiated after that (e.g., at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.	[245]
	Zhang et al.	Sulfonylureas	27 patients with acute basal ganglia hemorrhage	Sulfonylurea pretreatment before the onset of ICH	The pretreatment of sulfonylureas significantly reduced both PHE volume and rPHE.	[143]
	Corry et al.	Conivaptan	Seven patients	Administered every 12 hours for two days	Conivaptan can be administered safely to ICH patients. Although it evaluated the change in PHE, it did not compare patients without conivaptan.	[247]
	Zhao et al.	Remote ischemic conditioning	40 subjects with supratentorial ICH	Consecutive seven days after ICH	Improvement in the resolution rate of the hematoma and reduction in the relative PHE.	[248]
	Baker et al.	Therapeutic hypothermia	Multiple studies	Systematic review and meta-analysis	It is currently difficult to determine the extent of the harm caused by post-ICH fever. The cooling strategies used in the clinical studies were highly diverse. Definitive randomized controlled studies are still required to answer the therapeutic effects of hypothermia on PHE in ICH patients.	[140]

Abbreviations: ICH: intracerebral hemorrhage; ICP: intracranial pressure; PHE: perihematomal edema; PHER: expansion rate of perihematomal edema expansion rate; BP: blood pressure; SBP: systolic blood pressure; MMP-9: matrix metallopeptidase-9; rt-PA: recombinant tissue plasminogen activator; HICH: hypertensive intracerebral hemorrhage.