Glycaemia and ischaemia-reperfusion brain injury in patients with ischaemic stroke treated with mechanical thrombectomy (GLIAS-MT): an observational, unicentric, prospective study protocol

Introduction

Poststroke hyperglycaemia is a very common complication in ischaemic stroke, affecting approximately two-thirds of patients, and is associated with poorer recanalisation rates, reduced perfusion, increased damage due to ischaemia-reperfusion and, consequently, poorer patient outcomes.1 2 Furthermore, hyperglycaemia can counteract the potential therapeutic effect of reperfusion treatments such as intravenous thrombolysis3 4 and mechanical thrombectomy (MT).5–8

Hyperglycaemia can cause damage through several pathophysiological mechanisms, including abnormalities in the blood–brain barrier and increased lactic acid production.1 2 Poststroke hyperglycaemia has been independently associated with poor outcomes after MT, with lower rates of functional recovery,6 7 9 a higher risk of haemorrhagic transformation7 9 10 and cerebral oedema11 12 and increased mortality at 3 months.7 The GLycemia in Acute Stroke (GLIAS) study was the first multicentre study to establish prognostic threshold for hyperglycaemia at 155 mg/dL, demonstrating a correlation between elevated glucose levels in the acute phase of stroke and poor outcomes, independently of stroke severity, infarct volume, diabetes or age.13

In patients treated with MT, the Solitaire Flow Restoration With the Intention for Thrombectomy (SWIFT) clinical trial showed that for each 10 mg/dL increase in blood glucose values, there was a 42% reduction in the probability of an excellent recovery at 3 months.6 It has yet to be determined whether administering insulin therapy prior to and during MT can mitigate the negative impact of hyperglycaemia in stroke recovery. Several studies have attempted to analyse this impact based on retrospective discrete determinations, such as glycaemia on admission5 7 8 14 and 24–48 hours after stroke,15–17 but none of them have monitored glycaemia during the MT procedure.

Despite the mounting evidence of its deleterious effects, poststroke hyperglycaemia is currently undertreated, which could be due to the lack of specific recommendations.18–20 The Highly Effective Reperfusion using Multiple Endovascular deviceS (HERMES) collaboration highlighted the significant variation in glycaemic management guidelines during the acute phase of stroke across various MT clinical trials: four of the trials had no specific recommendations, and one advised against hyperglycaemia treatment.5 Periprocedural management primarily focuses on blood pressure optimisation and selection of anaesthetic technique while glucose-level control is usually relegated to the postprocedural phase.21 22 In daily clinical practice, glucose levels are not monitored during the procedure, despite being one of the main modifiable prognostic factors in the acute phase of ischaemic stroke and closely related to reperfusion damage. Determining the impact of poststroke hyperglycaemia on patient outcomes could, therefore, lead to a paradigm shift in clinical practice.

The development and use of subcutaneous continuous glucose monitoring (CGM) devices23 24 provides an excellent opportunity to investigate the prognostic impact of poststroke hyperglycaemia in patients with acute stroke. CGM devices are minimally invasive, measure glucose levels in the interstitial fluid every 5 min and have been shown to be safe in patients with stroke during research studies,25–29 including those treated with intravenous thrombolysis26 and, more recently, in patients who underwent endovascular therapy.30 The feasibility, diagnostic accuracy and safety of CGM in the anaesthetic setting have also been demonstrated.31

Few studies have analysed the effect of hyperglycaemia after stroke on the levels of biomarkers of brain damage and repair.32 Recently, a number of micro-RNAs (miRNAs) have been proposed to modify the response to ischaemia-reperfusion injury and to regulate the expression of several elements essential for cell survival and apoptosis. Consequently, there is a growing interest in the potential role of miRNAs as biomarkers of ischaemia-reperfusion injury and even as potential therapeutic targets.

These miRNAs are of interest due to their functions, with previous studies demonstrating a role in cerebral ischaemia. In the context of ischaemic stroke, miR-339, miR-15a, miR-424 and miR-100 have been associated with large vessel occlusion.33 34 MiR-339, which is overexpressed in cases of cerebral and myocardial ischaemia,35 is related to neuronal survival and suppression of apoptosis in ischaemic conditions.36 MiR-15 and miR-424 have been linked to an antiangiogenic effect through VEGF inhibition.37 Additionally, miR-100 has been demonstrated to have an antiatherosclerotic effect.38 Furthermore, this miRNA exhibits varying levels in patients with cerebral infarction due to large vessel occlusion, suggesting a potential association with functional recovery.33 Finally, miR-29b has been demonstrated to attenuate ischaemic injury by negatively regulating the p53-dependent apoptosis pathway and could, therefore, be a potential target in diminishing cell injury in ischaemic stroke.39

We hypothesised that those patients with glycaemia values <155 mg/dL during MT and especially at the time of reperfusion will have less ischaemia-reperfusion injury, showing a different miRNA expression profile, with better neurological and functional outcomes and a lower risk of haemorrhagic transformation and cerebral oedema.

Discussion

This study represents a further step in the consolidated research into the prognostic impact of hyperglycaemia after stroke that began with the GLIAS study, the first prospective multicentre study to show that the glycaemic threshold associated with poor prognosis in acute stroke patients is 155 mg/dL.13 The GLIAS study also helped to highlight the significance of identifying and treating persistent hyperglycaemia.40 The GLIAS-II study (PS09/01781), funded by the Carlos III Health Institute (ISCIII), demonstrated the high incidence of non-response to conventional glycaemic control in patients with acute stroke and its association with poor outcomes.18 The GLIAS-III study (PI18/00991), currently finished and undergoing data analysis, is a multicentre, translational study analysing the impact of glycaemic variability evaluated by CGM on the progression of cerebral infarction in patients and in an animal model.41

The GLIAS-MT study aims to demonstrate that the impact of hyperglycaemia at the time of recanalisation is a critical modifiable prognostic factor, associated with greater brain damage, a different miRNA expression profile as a biomarker of damage, and poorer neurological and functional outcomes.