Reactive oxygen species (ROS) scavengers were modestly neuroprotective in the acute period of intracerebral hemorrhage (ICH), according to a small randomized trial.
Perihematomal edema (PHE) expanded less with a 14-day course of N-acetylcysteine and selenium in the neurological ICU compared with placebo, reported Seungjoo Lee, MD, PhD, of Asan Medical Center in Seoul, Korea, and colleagues. Their manuscript was published online in Stroke.
That was true for both the edema volume (mean 21.90 vs 30.66 mL, P<0.01) and the ratio of volume at 2 weeks to that at baseline (1.19 vs 2.05, P<0.01).
However, brain hemorrhage volumes came out similar at 2 weeks with the ROS scavenger and placebo (mean 20.90 vs 18.70, P=0.74).
ROS scavenger recipients did reach target sedation levels faster (mean 5.98 hours vs 8.42 hours, P<0.01) and have shorter ICU stays (6.46 days vs 12.66 days, P<0.01) compared with the placebo group.
Yet 30-day functional outcomes on the modified Ranking Scale (mRS) didn’t improve more (scores 3.34 vs 3.53 with placebo), nor were total hospital stays shorter (20.28 vs 23.71 days).
“These results propose that our ROS scavengers are potent antioxidants with properties that mitigate PHE and functional outcomes in the acute period of patients with ICH,” Lee’s group maintained.
Like other critically-ill patients, people with ICH have oxidative stress that contributes to direct cellular injury. PHE is an imaging marker of secondary injury following ICH, and its clinical significance has been a subject of debate.
“Discovering treatments that mitigate secondary injury is a major unmet need in the uphill battle of reducing the global burden of death and disability from ICH,” according to Ashkan Shoamanesh, MD, and Aristeidis Katsanos, MD, PhD, both of the Population Health Research Institute at McMaster University in Hamilton, Ontario.
Lee’s trial joins a short list of ICH clinical randomized trials showing a reduction in PHE volume with intervention and thus “provides exciting novel results supporting the potential benefit and safety antioxidant therapy in this fight,” the pair wrote in an accompanying editorial.
“Although [the investigators’] findings are too preliminary to be implemented in clinical practice at this time, they are promising, supported by sound biological rationale, and warrant further exploration in large-scale clinical trials,” the editorialists concluded.
Lee’s group noted that ICH accounts for 10% and 27% of strokes and is associated with very high mortality and morbidity rates that have not budged in 30 years. No proven acute ICH therapies exist to date, as trial after trial has failed to show benefits to proposed medical and surgical interventions.
Their single-blind, randomized trial was conducted at several Korean centers. Eligible patients had spontaneous ICH and secondary ICH due to vascular anomalies, venous thrombosis, neoplasms, or hemorrhagic infarction (i.e., cases where hematoma and PHE can be measured on CT).
Lee and colleagues randomized 123 people to ROS scavengers (N-acetylcysteine 2000 mg/d and selenium 1600 µg/d IV for 14 days) or placebo starting within 24 hours of admission.
ROS scavenger and placebo groups shared similar baseline characteristics, including age (mean 54.4 vs 56.1 years) and sex (men 64.9% vs 53%). Initial hemorrhage volumes (34.78 vs 36.71 mL) and PHE volumes (18.47 vs 19.09 mL) were also comparable.
Hypertensive ICH was the most common type of ICH, accounting for over 40% of cases. Cerebrovascular disease was the second most common cause and was observed in 30%.
Study investigators reported no serious adverse events attributed to the ROS scavengers.
Their reasons for choosing N-acetylcysteine and selenium for this study, they said, included the abundance of existing safety data, their widespread availability, and low cost when compared with other ROS scavengers like edaravone and glutathione.
On top of the small sample size and single-blind design, the study couldn’t determine whether the observed effects of ROS scavengers were due to one alone or the combination of the two.
Another major limitation was the heterogeneous cohort of ICH subtypes studied, as Shoamanesh and Katsanos noted that “the pathophysiology of secondary ICH subtypes, such as hemorrhagic neoplasms and infarction, includes additional mechanisms of brain injury and edema that likely overshadow the relative contribution of the hemorrhage to neuroimaging and clinical outcomes.”
Furthermore, the literature suggests that ICH patients will need to be followed for at least 6 months to detect meaningful differences in the mRS, the editorialists added.
Nonetheless, the preliminary data from Lee’s group suggest that “PHE can be mitigated safely through supplemental antioxidant therapy with ROS scavengers,” they said.
The study was funded by a grant from the National Research Foundation of Korea.
Lee, Shoamanesh, and Katsanos had no disclosures.