BACKGROUND: The failures of recent studies intended to prevent cerebral 
vasospasm have moved the focus of research into delayed cerebral ischemia away 
from cerebral artery constriction towards other mechanisms. Recent accumulating 
evidence has suggested that early brain injury is also involved in the 
development of delayed cerebral ischemia, and that hydrogen can prevent early 
brain injury. Therefore, we have established a combination therapy of 
intravenous hydrogen infusion and intra-cisternal magnesium sulfate infusion for 
the treatment of both early brain injury and cerebral vasospasm. The present 
randomized controlled clinical trial is designed to investigate the effects of 
this novel therapeutic strategy on the occurrence of cerebral vasospasm, delayed 
cerebral ischemia, and clinical outcomes after high-grade subarachnoid 
hemorrhage.
METHODS: This study is a randomized, double-blind, placebo-controlled design to 
be conducted in two hospitals. A total of 450 patients with high-grade 
subarachnoid hemorrhage will be randomized to one of three arms: (i) Mg + H2 
group, (ii) Mg group, and (iii) control group. Patients who are assigned to the 
Mg + H2 group will receive intra-cisternal magnesium sulfate infusion 
(2.5 mmol/L) at 20 mL/h for 14 days and intravenous hydrogen-rich fluid infusion 
(200 mL) twice a day for 14 days. Patients who are assigned to the Mg group will 
receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 
14 days and intravenous normal glucose-electrolyte solution (200 mL) without 
added hydrogen twice a day for 14 days. Patients who are assigned to the control 
group will receive intra-cisternal Ringer solution without magnesium sulfate at 
20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) 
without added hydrogen twice a day for 14 days. Primary outcome measures will be 
occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary 
outcome measures will be modified Rankin scale score at 3, 6, and 12 months and 
biochemical markers.
DISCUSSION: The present protocol for a randomized, placebo-controlled study of 
intravenous hydrogen therapy with intra-cisternal magnesium infusion is expected 
to establish the efficacy and safety of this therapeutic strategy.
TRIAL REGISTRATION UMIN-CTR: UMIN000014696.