Is Neuroprotection Finally A Reality?Magnesium And Hydrogen in Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage remains a lethal disease, with 12% of patients dying at the ictus.1 Survivors, who present with poor grades, may also have a severe disability as the result of early brain injury (EBI) from high intracranial pressure and global cerebral hypoperfusion. EBI, however, is not the only problem since a large percentage also develops delayed cerebral ischemia, thought to be due mainly to cerebral vasospasm.2 A lot of research has been completed on the latter and less on the former. 

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Magnesium, with vasodilatory and neuroprotective effects (mainly via inhibition of glutamate excitotoxicity), has seemed a good candidate that could address both issues, but a large phase 3 randomized placebo-controlled study, the MASH-2 (Magnesium for Aneurysmal Subarachnoid Haemorrhage), found no beneficial impact of intravenous magnesium sulfate infusion starting within the first 4 days and continuing for up to 20 days after admission.3 One of the major concerns arising from this trial was that since magnesium does not cross the blood-brain barrier well, it is not available at the site where it could make the most difference. 

Higher doses might have reached that goal, but serious systemic side effects hinder achieving high serum and thus cerebrospinal fluid (CSF) concentrations. An alternative, but much less studied approach is early intervention on oxidative stress which plays a major role in EBI. Hydrogen has demonstrated antioxidant properties in experimental studies (through the reduction of highly toxic oxygen species and thus neuronal apoptosis) and is highly diffusible, reaching not only the brain but also subcellular compartments.4

No study, to our knowledge, has tackled both problems at the same time in this patient population. In this issue of the Journal, Takeuchi et al5 present the results of a small randomized placebo-controlled trial testing the safety and efficacy of magnesium sulfate infused during days 1 to 14 in the basal cisterns at a minimal dose necessary to achieve desired magnesium levels in the CSF. 

In a separate arm, other patients received an infusion of a hydrogen-enriched glucose-electrolyte solution intravenously in addition to the intracisternal magnesium. A third arm included controls, who were administered Ringers lactate intracisternal and nonhydrogenated glucose-electrolyte solution intravenously.

 All groups had a ventricular and a lumbar spinal drain to allow close monitoring of the intracranial pressure, to drain hydrocephalic fluid as needed, and to allow the intracisternal infusion to be drained out after circulating along the neuraxis. To be included and eventually randomized in the 3 arms in a 1:1:1 allocation, patients had to have Hunt and Kosnik scores of 4 to 5, but could not be Fisher grade 4 due to intracerebral hemorrhage or severe cerebral edema by neuroimaging. 

Because of concerns about the systemic effects of the solutions, patients with heart dysfunction or renal insufficiency were also excluded. Patients had to be treated by either clipping or coiling within 72 hours of their hemorrhage.

The groups were well matched with regard to comorbidities and potential risk factors for the worsened outcomes, such as smoking status and location of the aneurysm. This study, however, is heavily weighted toward securing the aneurysm by surgery, as only one of the 37 patients included underwent coiling and the rest had a surgical intervention; to provide intracisternal magnesium infusion in one patient who had to coil, a cisternal catheter was inserted via a supraorbital keyhole mini craniotomy. 

The patients who received the magnesium infusion had significantly higher CSF (but not serum) magnesium levels and were significantly less likely to have cerebral vasospasm or delayed cerebral ischemia. In addition, those patients who received the combination therapy with magnesium and hydrogen infusions had lower levels of serum malondialdehyde, a marker of oxidative stress, compared with controls, and those on magnesium-only infusion had lower neuron-specific enolase, a marker of neuronal injury, compared with controls in both serum and CSF. 

No systemic complications occurred with either the intracisternal magnesium or the combination with hydrogen; the central nervous system complications (including meningitis, hydrocephalus, or re-rupture) were not different between the 3 groups. Furthermore, at 1-year follow-up, a higher percentage of patients in the 2 treatment arms achieved good to excellent functional outcomes, as determined by the modified Rankin Scale, and higher independence, as assessed by the Barthel index. Certainly, this single, low-volume center (151 patients with aneurysmal subarachnoid hemorrhage treated over 4 years) study with a very small number of patients in each arm raises concerns for external validity. 

Continental differences in the management of aneurysmal subarachnoid hemorrhage may also affect the results: the standard of care for managing patients with subarachnoid hemorrhage in Japan and China is to use fasudil, a RhoA/Rho-kinase inhibitor that leads to decreased vasoconstriction, instead of nimodipine as is the case in Europe and North America. Also, the treatment modality used in the study differs from the current practice in the Western World of endovascular treatment in a large percentage of patients. Except for a single patient treated with coiling, all the other 36 patients were treated surgically. 

During the procedure, a cisternal catheter was placed to infuse the magnesium and this might have affected the selection of treatment to secure the aneurysm a priori even though coiling was not an exclusion. Placement of a cisternal catheter in patients with coiling was achieved by inserting a catheter through a procedure that is rarely done in the rest of the world. The protocol as carried out in the study is also complicated, including infusion and contemporaneous lumbar spinal and ventricular or cisternal drainage (which by itself may affect the outcomes by removing subarachnoid blood6 ) but should be well within the capacity of a standard neurointensive care unit. 

There are also several unanswered questions based on the design of this study. What are the optimal infusion rate and the lowest magnesium concentration in the CSF to have the same positive effects? How long should the infusion last? Is it possible to decrease it to allow earlier removal of those catheters and potentially decrease the risk for meningitis, which occurred in 11% of the patients? Could the hydrogen be inhaled instead of infused, for example, immediately after admission or even intubation, to have an earlier effect on EBI? Should we have a randomized study including a hydrogen arm only? What are the interactions, if any, between magnesium and hydrogen? Could the positive effects of intracisternal magnesium be extended to better-grade aneurysmal subarachnoid hemorrhage patients, who may not experience EBI to the severity that poor grades do? If there is nonobstructive hydrocephalus and external ventricular drainage is placed, could we instill intraventricular magnesium and clamp the drain for a while to allow cisternal levels to build up in coiled patients with or without lumbar drainage? 

With all of these concerns in mind, it is still encouraging to see data that confirm safety and demonstrate a real possibility of neuroprotection for intracisternal infusion of magnesium and with a promising additional effect of intravenous hydrogen. The authors were able to demonstrate an appropriate CSF level of magnesium without an equivalent systemic rise. There were no systemic complications of elevated magnesium, which may have interfered in previous trials with assessing the effectiveness of its neuroprotection. 

These data argue a need for a larger, multicenter, and international trial, which will be able to adjust for treatment differences, such as fasudil versus nimodipine, or approaches, such as intracisternal versus intraventricular infusion. It will be important to see if there is an interaction with nimodipine, and whether this invasive protocol is justified in patients who are otherwise receiving less invasive endovascular care for their aneurysms or present with lower Hunt and Kosnik score and develop vasospasm at a later time.

Cistanche neuroprotection effect

Cistanche is a plant extract known for its neuroprotective properties, and its mechanism of action is believed to involve antioxidant, anti-inflammatory, and antiapoptotic effects. There are several relevant tests and application cases related to the neuroprotective effects of Cistanche, which include:

1. In vitro studies: In vitro studies have shown that Cistanche extract protects neurons from stress-induced damage by reducing oxidative stress and inflammation.

2. Animal studies: Animal studies have demonstrated that Cistanche can protect against neuronal damage caused by cerebral ischemia, traumatic brain injury, and neurotoxin exposure.

3. Human studies: There is limited clinical evidence on the neuroprotective effects of Cistanche in humans, but some studies have suggested that it may improve cognitive function and reduce age-related decline in memory.

REFERENCES 

1 Huang J, van Gelder JM. The probability of sudden death from rupture of intracranial aneurysms: a meta-analysis. Neurosurgery. 2002;51:1101– 1105. doi: 10.1097/00006123-200211000-00001 

2. de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer TA, Abrahamson S, Macdonald RL. The critical care management of poor-grade subarachnoid hemorrhage. Crit Care. 2016;20:21. doi: 10.1186/s13054-016-1193-9

3. Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, van Oostenbrugge RJ, Al-Shahi Salman R, Lavados PM, Rinkel GJ, et al; MASH-2 Study Group. Magnesium for aneurysmal subarachnoid hemorrhage (MASH-2): a randomized placebo-controlled trial. Lancet. 2012;380:44–49. doi 10.1016/S0140-6736(12)60724-7 

4. Dixon BJ, Tang J, Zhang JH. The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res. 2013;3:10. doi: 10.1186/2045-9912-3-10 

5. Takeuchi S, Kumagai K, Toyooka T, Otani N, Wada K, Mori K. Intravenous hydrogen therapy with intracisternal magnesium sulfate infusion in severe aneurysmal subarachnoid hemorrhage. Stroke. 2020 

6. Hänggi D, Liersch J, Turowski B, Yong M, Steiger HJ. The effect of lumboventricular lavage and simultaneous low-frequency head-motion therapy after severe subarachnoid hemorrhage: results of a single center prospective phase II trial. J Neurosurg. 2008;108:1192–1199. doi: 10.3171/JNS/2008/108/6/1192

Colum F. Amory, MD, MPH; Panayiotis N. Varelas , MD, PhD