Glibenclamide for Brain Edema


  • Following ischemic insult, SUR1-TRPM4 ion channel expressed in all cells of the neurovascular unit.
  • Early stages of ischemia, channel upregulation occurs at the luminal and abluminal surfaces of the vascular endothelium, mediating an ionic gradient from the intraluminal space to the interstitial space.
  • Water transported from vasculature into the parenchyma.
  • Formation of ionic gradient followed by or accompanied by breakdown of the BBB.
  • Capillary structure is maintained, preventing extravasated of cells, while vasculature becomes open to water movement and movement of macromolecules s.a. Immunoglobulin / albumin.
  • Opening facilitates osmotic and hydrostatic movement of water into brain.
  • Tight junctions between vascular endothelial cells degraded by MMP9, which further facilitates fluid movement into the brain.


  • Glibenclamide is an anti-edema drug.
  • Glibenclamide blocks the activity of the SUR1-TRPM4 ion channel.
  • This channel is upregulated in the CNS only after ischemia / trauma.
  • Glibenclamide blocks this cascade, protects the neurovascular unit.
  • First impact is on the capillary endothelium, rather than neurons.
  • Glibenclamide does not cross the uninjured BBB, only the channels up-regulated in the vascular endothelium are relevant until such time as the BBB is disrupted.


Jacobson, S., MacAllister, T. and Geliebter, D., 2020. Found in translation: The rationale behind the early development of glibenclamide in large hemispheric infarction. Neuroscience Letters, 716, p.134672.

Recommendations for Thromboprophylaxis in Hospitalized COVID Patients



Hospitalized COVID AC Recs.May2020


Northwell Health COVID19 and Guidance on Management of Antithrombotic Therapy; Dr. Alex C. Spyropoulos System Director – Anticoagulation and Clinical Thrombosis Services; Graphic Editor: Dr. Rachel-Maria Brown, Director – Inpatient Cardiac Services

Risk Score to Predict QTc Prolongation in Hospitalized Patients

For patients with COVID-19, we are using drugs that prolong QT-interval.  The risk of life-threatening arrhythmias from QT prolongation may be higher.  This article reports a scoring system to identify patients that are at risk for QT prolongation.

The study found that the following factors predicted QTc prolongation:  female, sepsi, LV dysfunction, administration of QT-prolong drug, >= 2 QT prolonging drugs, loop-diuretic, age >68, serum K <3.5, admitting ATc >450ms.

A risk score was developed.  Risk was classified as low (score of 0-6), moderate (7-10) and high (11-21).



A high risk score >11 was associated with 74% Sn and 77% Sp (PPV 79% NPV 76) for predicting QTc prolongation.  Incidence of QTc prolongation 15% in low risk, 37% in moderate risk and 73% in high risk.










Tisdale, J., Jaynes, H., Kingery, J., Mourad, N., Trujillo, T., Overholser, B., & Kovacs, R. (2013). Development and Validation of a Risk Score to Predict QT Interval Prolongation in Hospitalized Patients. Circulation: Cardiovascular Quality And Outcomes, 6(4), 479-487. doi: 10.1161/circoutcomes.113.000152

COVID-19 Acute Necrotizing Encephalopathy

Case report: COVID-19 associated acute necrotizine hemorrhagic encephalopathy – ANE – associated iwth other viral infections.  Female, late 50s, 3-day cough, fever, altered mental status.

Work-up NEG for influenza, nasopharyngeal swab (+) coronavirus, CSF limited – traumatic LP, CSF bacterial culture NG, HSV HSV 1 and 2, varicella, WNV NEG; unable to test CSF for SARSCoV-2.

CT head:   symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram

MRI: hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions

Acute necrotizing encephalopathy

  • rare complication of influenza / viral infections
  • related to intracranial cytokine storms –> BBB breakdown
  • no direct viral invasion or parainfecitous demyelination
  • reported mostly in pediatric population but occurs in adults as well

Imaging Features

  • symmetric, multifocal lesions with invariable thalamic involvement
  • Other commonly involved locations include the brain stem, cerebral white matter, and cerebellum
  • hypoattenuating on CT
  • MRI shows T2 FLAIR hyperintense signal with internal hemorrhage
  • Postcontrast images may demonstrate a ring of contrast enhancement



Image from noncontrast head CT demonstrates symmetric hypoattenuation within the bilateral medial thalami (arrows). B, Axial CT venogram demonstrates patency of the cerebral venous vasculature, including the internal cerebral veins (arrows). C, Coronal reformat of aCT angiogram demonstrates normal appearance of the basilar artery and proximal posterior cerebral arteries.


MRI images demonstrate T2 FLAIR hyperintensity within the bilateral medial
temporal lobes and thalami (A, B, E, F) with evidence of hemorrhage indicated by hypointense signal intensity on susceptibility-weighted images (C, G) and rim enhancement on postcontrast
images (D, H).



Poyiadji, N., Shahin, G., Noujaim, D., Stone, M., Patel, S., & Griffith, B. (2020). COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features. Radiology, 201187. doi: 10.1148/radiol.2020201187

SCCM Guidelines on COVID-19 Management – summarized

SCCM released a guideline on the management of COVID-19.  For those pressed for time, I’ve condensed the guidelines into a 13-page Q&A format.  The questions are formulated by me based on the guideline content and the answers are lifted from the SCCM guidelines, some of which I have reformatted from passive to active voice for easier reading.  Please reference the original guideline text, or message me if there are any errors.


(download PDF file here)


Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Waleed Alhazzani, Morten Hylander Møller, Yaseen M. Arabi , Mark Loeb, Michelle Ng Gong, Eddy Fan, Simon Oczkowski, Mitchell M. Levy, Lennie Derde, Amy Dzierba, Bin Du, Michael Aboodi, Hannah Wunsch, Maurizio Cecconi, Younsuck Koh, Daniel S. Chertow, Kathryn Maitland, Fayez Alshamsi, Emilie Belley-Cote, Massimiliano Greco, Matthew Laundy, Jill S. Morgan, Jozef Kesecioglu , Allison McGeer, Leonard Mermel, Manoj J. Mammen, Paul E. Alexander, Amy Arrington, John Centofanti, Giuseppe Citerio, Bandar Baw, Ziad A. Memish, Naomi Hammond, Frederick G. Hayden, Laura Evans, Andrew Rhodes

Hydroxychloroquine and Azithromycin for COVID-19

The group of Philippe Gautret (IHU-Méditerranée Infection, Marseille, France) presented their results on a non-randomized clinical trial using two antibacterial agents – hydroxychloroquine and azithromycin – for the treatment of COVID-19.

The results are promising, but the number of patients enrolled is small, and the study is not a randomized clinical trial.  Also, 6 of 26 patients in the treatment group were lost to follow-up, and no intention treat analysis has been included yet in the initial report.

The idea to use hydroxychloroquine, was based on a trial conducted in Chinese patients with COVID19 which showed a significant effect of chloroquine (an old antimalarial drug) on viral clearance as well as clinical outcome.  The dosing regimen for chloroquine was 500mg twice a day for ten days.

Hydroxychloroquine, which is an analogue of chloroquine, has been demonstrated to have anti-SARS-CoV activity in vitro, and has a better safety profile than chloroquine.

Azithromycin has been showed to be active in vitro against Zika and Ebola viruses, and prevent severe respiratory tract infections when given to patients with viral infection.

This study enrolled hospitalized patients older than 12 years old with documented SARS-CoV-2 carriage in nasopharyngeal sample on admission.  Patients with allergy or known contraindications to the drug (s.a. retinopathy, G6PD deficiency, QT prolongation) were excluded, as well as pregnant or breastfeeding patients.

The primary endpoint was virological clearance on day 6.

The treatment regimen is hydroxychloroquine sulfate PO 200 mg TID x 10 days.  The patients who refused treatment or were excluded based on criteria served as controls to the treatment group. Azithromycin was given to 6 patients (not part of the protocol) to prevent bacterial infection, at  a dose of 500mg PO x 1 then 250mg/day x 4 days.

Results of preliminary data showed that 70% of treatment group were virologicaly cured at day 6, compared with 12.5% in the control group (p = 0.001).  Subgroup analysis of patients who received both hydroxychloroquine and azithromycin showed that 100% of patients treated with both antibiotics were virologicaly cured, compared to 57.1% of patients treated with only hydroxychloroquine and 12.5% in the control group (p<0.001).

The study proposes that nasopharyngeal carriage of SARS-CoV2 can be cleared in 3-6 days in most patients.  Of note, mean duration of viral shedding (based on data from COVID cases in China) was 20 days (and up to 37 days).

Figure below:  percentage of patients with (+) nasopharyngeal samples through day 6.

Figure below:  percentage of patients with (+) nasopharyngeal samples through day 6.  Treatment group divided into 2 subgroups – hydroxychloroquine +/- azithromycin.


Raw data provided in the supplemental tables.  I colorized the table to show clearly why the data seems promising, with the limitations as discussed above.




Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of
COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of
Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949