Discussion
Following an aSAH, it can cause substantial cerebral oedema, thereby elevating the mortality rate associated with aSAH.6 This occurs due to early ischaemic brain injury and subsequent disruption of the blood-brain barrier, resulting in cellular swelling. The opening of the SUR1-TRPM4 channel may further contribute to cytotoxic brain oedema and vascular brain oedema.21 Glibenclamide, functioning as an inhibitor of the SUR1 receptor, has demonstrated its potential to mitigate cerebral oedema and provide neuroprotective effects in various central nervous system injuries, including ischaemic conditions,22–24 as well as haemorrhagic cerebrovascular diseases.15 25 26 To the best of our knowledge, this is the first randomised controlled trial assessing the efficacy of high-dose oral glibenclamide in addressing cerebral oedema following aSAH. The primary outcome was SEBES, a composite assessment that incorporates clinical scores, radiological evaluations and monitoring parameters from both plasma and cerebrospinal fluid to predict and analyses functional outcomes subsequent to aSAH. Our study demonstrates that oral glibenclamide notably increases the proportion of cases characterised by mild cerebral oedema as well as those showing favourable bleeding volume assessments defined by the modified Fisher scale, in comparison to the placebo group. It improves the SEBES distribution among aSAH patients. Furthermore, the treatment enhances the proportion of patients achieving a favourable long-term functional prognosis. However, it is associated with an increased risk of hypoglycaemia. Importantly, no significant differences in other adverse events were observed between the two groups. Moreover, the SUR1-TRPM4 indicators that we monitored exhibited distinct variations, corresponding to radiological findings, thereby underscoring the significant advantage of glibenclamide in ameliorating cerebral oedema. This study introduces a novel treatment strategy, providing a comprehensive analysis of the efficacy and safety of higher doses of glibenclamide across various dimensions and supported by more extensive evidence.
Previous clinical studies have demonstrated that intravenous glibenclamide yielded suboptimal outcomes and did not exhibit significant effects when administered at dosages of 2.5 mg/day for traumatic brain injury,27 5 mg/day for acute ischaemic stroke20 and 5 mg/day for aSAH.17 However, for moderate and severe traumatic brain injury, a dosage of 10 mg/day was found to reduce contusion expansion rates.28 In light of these findings, we determined that a daily dosage of 15 mg was appropriate. It is worth noting that previous reports have confirmed the safe administration of glibenclamide at various dosages, ranging from 2.5 mg/day to 20 mg/day, within clinical settings.29
The clinical interventions and long-term prognosis for patients with aSAH vary depending on the disease’s severity and the occurrence of secondary brain injury. Our assessment of the clinical severity of aSAH patients on admission relied on the Hunt-Hess and WFNS grading systems. To provide robust radiological evidence, we favoured the use of head CT scans. These scans not only reveal the extent of cerebral oedema but also pinpoint the location and severity of bleeding, which is crucial for diagnosis. For assessing cerebral oedema, we employed the SEBES, which proved to be effective.19 The modified Fisher scale was used to evaluate the extent of bleeding in aSAH cases, with higher scores correlating with an increased risk of cerebral vasospasm. This scoring system holds predictive value in anticipating cerebral vasospasm.30 Importantly, we did not interfere with clinical physicians’ decisions regarding treatment responses based on their assessment of the patients’ condition. The probability of undergoing decompressive craniectomy surgery on admission was similar between the two groups of patients with cerebral oedema (14.3% vs 7.1%, p=0.669).
The primary outcome revealed a significant improvement in cerebral oedema in the glibenclamide group following medication. Notably, on admission, patients in the glibenclamide group exhibited more pronounced cerebral oedema compared with the placebo group, as evidenced by higher WFNS and mRS scores, as well as a greater likelihood of requiring decompressive craniectomy. However, after 10 days of medication, the incidence of patients in the glibenclamide group necessitating decompressive craniectomy was lower (3.6% vs 7.1%, p=1.000), with one patient in the placebo group undergoing bilateral decompressive craniectomy. Although not statistically significant, this analysis indirectly suggests the advantage of glibenclamide in ameliorating cerebral oedema and reducing the need for secondary procedures. Decompressive craniectomy is a recognised treatment for addressing cerebral oedema. However, a preclinical study demonstrated that in an ischaemia model, glibenclamide was as effective as decompressive craniectomy in preventing death from malignant cerebral oedema but outperformed it in preserving neurological function and the integrity of watershed cortex and deep white matter.11 These findings align with the results of our trial.
The secondary outcomes reveal an interesting trend in the glibenclamide group, where the proportion of patients showing improved functionality increased over time. This observation diverges somewhat from the findings of previous trials.20 27 31 Those trials suggested that glibenclamide led to better functional outcomes at the time of discharge. In our trial, we did not observe significant improvement at discharge. Nevertheless, when considering long-term prognosis, our trial demonstrated a growing proportion of patients benefiting from glibenclamide. Analysis of the modified Fisher scale indicated that patients treated with glibenclamide experienced faster absorption of intracranial haemorrhage. However, the occurrence of adverse complications such as cerebral vasospasm did not exhibit significant differences when compared with the placebo group. This conclusion is in line with the results of a previous randomised controlled trial.17 Additionally, glibenclamide did not elevate the incidence of other adverse events in patients, nor did it substantially prolong the length of hospital stays. Glibenclamide did not reduce the mortality rate in aSAH patients, which aligns with the results of previous studies.17 24 26
Active transportation relies on a continuous supply of ATP to provide energy, such as Na+/K+-ATPase and Ca2+-ATPase. Although both KATP and SUR1-TRPM4 channels are regulated by SUR1, they have opposite functional effects in central nervous system injury. The opening of selective KATP channels causes cell hyperpolarisation and may have neuroprotective effects, while the opening of non-selective SUR1-TRPM4 channels causes cell depolarisation.32 The opening of SUR1-TRPM4 channels is associated with excessive influx of Na+, accompanied by the influx of Cl− and H2O, causing osmotic cell swelling (cytotoxic oedema). If severe, it leads to cell necrosis.25 Pathological activation of the SUR1-TRPM4 channel can also mediate the disruption of the blood-brain barrier, disrupting the tight connections between cells and leading to vascular oedema.15 Secondary injury ultimately leads to complete loss of capillary structure and enters the haemorrhagic transformation. After the rupture of an aneurysm, blood extravasation produces thrombin and methemoglobin at the injury site, which independently mediate delayed angiogenic oedema.33 SUR1-TRPM4 channel leading to endothelial cell infiltrating death is also a factor in the formation of haemorrhagic transformation, leading to delayed vascular oedema.22 Our results indicate that oral high-dose glibenclamide significantly reduces plasma TRPM4 levels, bringing the concentration as close as possible to normal intracranial pressure patients with hydrocephalus. Sheth KN24 found similar results regarding the association between elevated MMP-9 levels and cerebral oedema after ischaemic stroke, with glibenclamide reducing the concentration of MMP-9 in plasma. This indicates that glibenclamide acts as an inhibitory channel in the blood, but its research fails to indicate intracranial conditions. We observe the concentration of SUR1-TRPM4 in the cerebrospinal fluid and find that patients with glibenclamide significantly increased, while the placebo group tended to approach patients with hydrocephalus. We also observed that patients in the glibenclamide group were more likely to require cerebrospinal fluid shunting within 7 days (46.4% vs 25.0%, p=0.094). We speculate that apoptotic processes are clearly enhanced after glibenclamide treatment in SUR1 cells,34 and remains in the cerebrospinal fluid and accumulates in the ventricles, leading to ventricular enlargement in patients with glibenclamide. Clinicians then perform cerebrospinal fluid shunt, but glibenclamide does not cause the occurrence of malignant hydrocephalus. AQP1 and Na+/K+/Cl– co-transporter have an important role in choroid plexus injury-induced cerebrospinal fluid hypersecretion and hydrocephalus after SAH,35 which is different from the mechanism of glibenclamide and needs further investigation. Here, we consider that the levels of SUR1-TRPM4 in the plasma of patients with normal intracranial pressure hydrocephalus are close to those of normal individuals, while belonging to a pathological process in cerebrospinal fluid. Therefore, the concentration of SUR1-TRPM4 in cerebrospinal fluid is highly similar to that of the placebo group.
The limitations of this study primarily revolve around the small sample size. In order to enhance the radiological evaluation of cerebral oedema, additional indicators such as the measurement of haematoma volume should be incorporated. Future investigations into glibenclamide should aim to minimise the duration of administration, as these variables may potentially lead to an underestimation of glibenclamide’s efficacy in terms of achieving positive functional outcomes at the 6-month mark. Furthermore, there is a notable absence of assessments pertaining to cognitive improvement. It is imperative to acknowledge that global cerebral oedema represents a crucial risk factor for cognitive dysfunction following SAH. Therefore, treatment strategies targeting brain swelling hold significant promise for ameliorating cognitive outcomes post-SAH.7 It is important to note that high doses of oral glibenclamide carry the potential risk of inducing severe hypoglycaemia, and its usage is subject to considerable individual variation. Consequently, it is imperative to rigorously adhere to the designated treatment protocol, and it is strongly recommended to employ intravenous micropumps to regulate the infusion rate for enhanced safety.
In summary, the administration of oral high-dose glibenclamide yielded noteworthy reductions in the radiological assessment of cerebral oedema and bleeding following a 10-day medication regimen. Significant alterations were also observed in the concentrations of SUR1-TRPM4 in both plasma and cerebrospinal fluid. While glibenclamide may not exhibit a substantial impact on overall mortality rates, it does demonstrate the potential to influence the distribution of patients with a favourable functional prognosis. However, it is worth noting that the use of glibenclamide is associated with an elevated incidence of hypoglycaemia. These findings underscore a potential role for glibenclamide in the pathogenesis of brain swelling following aSAH and advocate for further investigation through larger-scale studies in this context.