Table 2.
Summary of key clinical trials and meta-analysis of cerebral edema in acute intracerebral hemorrhage.
| Intervention | References | Method | Findings |
|---|---|---|---|
| Osmotic agents | |||
| Mannitol | Sun et al. (2018) | •Meta analysis of 34 studies •N = 3,627 •Mannitol vs. control |
•No recommendation for use of mannitol in early stages of supratentorial hypertensive intracranial hemorrhage in the absence of clinical signs of intracranial hypertension |
| BP-lowering agents | |||
| Multiple agents | Anderson et al. (2013) | •N = 270 •Intensive (<140 mm Hg) vs. guideline-based (<180 mm Hg) BP management |
•Attenuated hematoma growth at 72 h •No clear effect on perihematomal edema |
| Gong et al. (2017) | •Meta-analysis of 6 studies •N = 4,395 •Intensive vs. guideline based |
•No significant differences in primary outcomes measures between groups •Higher risk of renal adverse events in intensive group |
|
| Tsivgoulis et al. (2014) | •Meta-analysis of 4 studies •N = 3,315 •Intensive vs. guideline-based |
•Reduction in absolute hematoma expansion at 24 h | |
| Moullali et al. (2022) | •Meta-analysis of 50 trials •N = 11,494 •Intensive vs. guideline based |
•No overall benefit on functional outcome | |
| Nicardipine | Leasure et al. (2019) | •Phase III •N = 1,000 •IV nicardipine targeting 3 tiers of SBP: 170–199, 140–169, or 110–139 mm Hg |
•Reduction of hematoma expansion and 24-h perihematomal edema ratio in deep ICH •No effect on poor 3-month outcome |
| Hematoma volume reduction-neurosurgery | |||
| Decompressive Craniectomy (DHC) | Yao et al. (2018) | •Meta-analysis: one RCT and 7 observational studies •DHC vs. control •N = 286 |
•DHC significantly reduced mortality rates in those with spontaneous ICH •Not associated with higher rates of postoperative rebreeding or hydrocephalus |
| Hematoma evacuation | Okuda et al. (2006) | •N = 16 •Putaminal hemorrhage •Surgical evacuation vs. conservative treatment |
•Hematoma volume reduced by surgery reduces cerebral edema |
| Early Surgery | Mendelow et al. (2005) | •N = 1,033 •Early surgery (within 24 h of randomization) vs. conservative treatment (later evacuation was allowed) •GSC 5 or more; hematoma volume >2 cm •Surgical method: craniotomy, burr hole, endoscopy or stereotaxy |
•No differences mortality at 6 months •No statistically significant differences in prognosis based on Rankin scale, Barthel index or Glasgow |
| Mendelow et al. (2013) | •N =170 •Only traumatic brain injury patients (parenchymal hematomas) •Within 48 of TBI •Hematoma volume > 10 ml •Early surgery (within 12 h of randomization) vs. conservative treatment (later evacuation was allowed) |
•Greater survival rate (85% vs. 67%) •6-month outcome (GOS): No significant benefit |
|
| Gregson et al. (2012) | •Individual patient data subgroup meta-analysis •N = 2,186 •Surgical vs. conservative management |
•Improved outcome (p < 0.05) with surgery if performed within 8 h or ICH volume of 20 to 50 ml or GCS 9-12 or age 50–69 years | |
| Burr hole craniectomy | Zuo et al. (2009) | •N =176 •Hypertensive basal ganglia hematoma •Gross-total removal vs. sub-total hematoma evacuation |
•Significant greater reduction in edema in the complete evacuation group •Higher Barthel index in the complete evacuation group (p < 0.05) |
| MIS plus rtPA | Mould et al. (2013) | •N = 79 surgical (hematoma removal using MIS and r-tPA or only surgery) vs. N = 39 medical | •Lower edema volume at end of treatment •Correlation between reduction in edema and percentage of ICH removal |
| MIS | Xia et al. (2018) | •Meta analysis: 5 RCTs and 9 controlled studies •N = 2,466 •MIS vs. conventional craniotomy |
•MIS was associated with lower rates of rebleeding, better functional recovery •Mortality rates were significantly lower in the MIS group |
| Anti-inflammatory interventions | |||
| Celecoxib | Lee et al. (2013) | •N = 44 •within 24 h of ICH •Celecoxib 400 mg BD for 14 days vs. control |
•Celecoxib was associated with a smaller expansion of ICH |
| Dexamethasone | Wintzer et al. (2020) | •Meta-analysis of 7 RCTs •N = 490 |
•No significant benefit or harm of dexamethasone has been established |
| Fingolimod | Fu et al. (2014) | •N = 23 •Fingolimod 0.5 mg orally once a day for 3 days vs. standard care |
•Fingolimod reduced relative PHE at day 7 and 14 •No differences in ICH volume |
| Magnesium | Saver et al. (2013) | •N = 1,700 •IV Mg sulfate or placebo within 2 h |
•No improvement in functional outcomes at 90 days •Effects on edema volume unknown |
| Memantine | Bakhshayesh et al. (2014) | •Memantine 10 mg orally daily for a month and then increased to 20 mg daily for 2 months vs. placebo | •Improvement in neurological outcome at 90 days |
| Minocycline | Fouda et al. (2017) | •N = 16 •Within 24 h of onset •400 mg of IV minocycline, followed by 400 mg oral daily for 4 days |
•No differences in inflammatory biomarkers (MMP-9, interleukin-6, iron, ferritin, total iron binding capacity), hematoma volume, or perihematomal edema |
| Targeting erythrocytes degradation products | |||
| Deferoxamine (DFO) | Selim et al. (2019) | •Phase II •N = 291 •DFO 32 mg/kg/day for 3 consecutive days vs. placebo |
•No significant difference on outcome at 90 days •No increased severe adverse events, major disability, or death •No effect on relative PHE growth |
BD, ‘bis in die' meaning twice a day; BP, blood pressure; DFO, deferoxamine; DHC, decompressive hemicraniectomy; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale; h, hours; ICH, intracerebral hemorrhage; Mg, magnesium; MIS, minimally invasive surgery; MMP, matrix metalloproteinase; PHE, perihematomal edema; RCT, randomized controlled trial; r-TPA, recombinant tissue plasminogen activator; TBI, traumatic brain injury; TNF, tumor necrosis factor; TXB2, thromboxane B2; vs., versus.