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IV glibenclamide shows promise for reducing cerebral edema and appears to be safe. PO glyburide leads to more hypoglycemia, especially if abnl renal fxn. Smaller, more frequent dosing may help. Kudos to @MikeA_42 for pushing this through to publication. https://www.sciencedirect.com/science/article/pii/S187887502032492X
@jessestokum performed work in Dr. Marc Simard's lab demonstrating how SUR1-TRPM4 and AQP4 form a complex that amplifies ion/water osmotic coupling and drives astrocyte swelling after brain injury. @UMDNeurosurgery . https://onlinelibrary.wiley.com/doi/full/10.1002/glia.23231?casa_token=ez6BkDxfRJwAAAAA%3Ayc6hGZWCzz8Lvq4uZTf-jElfM9Ib3jVmtCO_YzotENVKJ-cIJmrUia8uPi6um3H2jBlbPTtqcBaVOvl_Zw#.YBQicYbemoo.twitter
The role of Sur1-TRPM4 and AQP4 in the milieu that drives cerebral edema was recently summarized nicely by @MDNeurocritcare fellow Melissa Pergakis. https://www.tandfonline.com/doi/abs/10.1080/14656566.2021.1876663?forwardService=showFullText&tokenAccess=KRJBPGCNZ9DDQJBUVCTZ&tokenDomain=eprints&doi=10.1080%2F14656566.2021.1876663&target=10.1080%2F14656566.2021.1876663&journalCode=ieop20#.YBQgWjW_taM.twitter
Preclinical models show glibenclamide AKA glyburide inhibits Sur1, reduced cerebral edema, and improves neurological function https://pubmed.ncbi.nlm.nih.gov/24132564/
Retrospective study of patients with diabetes shows that those on sulfonylureas prior to their stroke had improved outcomes compared to those on other glycemic control agents. https://pubmed.ncbi.nlm.nih.gov/17673715/
The Games-RP trial led by @sheth_kevin and @wtkimberly showed that iv glibenclamide reduced cerebral edema and mortality attributed to edema, but did not achieve primary outcome (# of pts with good outcome without undergoing hemicrani). https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30196-X/fulltext#.YBQqWzISrtg.twitter
Games-RP found no difference in hypoglycemia (glucose < 55.8 mg/dL) between groups (9% vs. 0%, p =.12). using IV glibenclamide infusion. There was no symptomatic hypoglycemia in the study.
In contrast, in our retrospective review of PO glyburide use (2.5 mg bid) we found that 23.9% of patients experienced hypoglycemia! Impaired renal function was the major risk factor while high BMI seemed protective.
Why the discrepancy? PO glyburide has narrow therapeutic index, highly variable bioavailability, and serum concentration depends on gastric pH which varies widely in ICU patients.
Does hypoglycemia matter? NICE-SUGAR trial showed aOR for death of 1.41 and 2.10 for moderate and severe hypoglycemia, respectively. https://www.nejm.org/doi/full/10.1056/NEJMoa0810625#.YBQucqje_Js.twitter
Hypoglycemia could be even more injurious in brain injury where it is linked to brain energy crises and increased mortality. https://journals.lww.com/ccmjournal/Abstract/2008/12000/Impact_of_tight_glycemic_control_on_cerebral.16.aspx
So be careful with po glyburide! If using, consider frequent glucose checks and smaller, more frequent doses (1.25mg q6h). Limit use in patients with renal dysfunction, low bmi, decrease in nutritional support.
CHARM study currently evaluating IV glibenclamide's effect on 90 day mRS after LHI. If positive study, perhaps we should all have access to IV formulation. https://clinicaltrials.gov/ct2/show/NCT02864953
Let me know if you found this to be helpful! @MikeA_42 @drdangayach @JesseStokum @sheth_kevin @wtkimberly @MDNeurocritcare #neurotwitter #FOAMed #meded @WorldNeurosurg @neurocritical @EricLawson90 @AaronLBerkowitz @aartisarwal @ColumbiaNCC
