Glibenclamide for Brain Edema

PATHOPHYSIOLOGY OF CEREBRAL EDEMA IN STROKE:

  • 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.

MECHANISM OF ACTION OF GLIBENCLAMIDE

  • 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.

Reference:

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.

Headache After SAH

Headache after SAH increases in intensity during first 7d after onset.

Mechanism:

  • factors that contribute to vasopasm may also lead to headache
  • chemical irritation of blood on meninges and subarachnoid space can cause pain
  • infiltration of immune cells, immune activation and inflammatory cytokines contributes to pain
  • alterations in brain perfusion from vasopasm may also be a factor

 

Treatment:

  • Fioricet largely ineffective, ?associated with early vasospasm
  • In SAH patients, elevated Mg levels associated with less severe headache, – IV magnesium therapy may provide relief for SAH patients?
    • Magnesium is a non-competitive antagonist of voltage-dependent calcium channels and NMDA receptor.  Blocking of NMDA receptor is involved in pain modulation – prevents induction of central pain sensitisation. 
    • The effect of magnesium on headache after SAH is unknown. 
    • Most studies use dose of 1-2G IV bolus, in the study referenced below, higher daily dose (16G MgSO4 for a sustained period – nonbolus) was given. 
    • Diarrhea is a common side effect.

 

AP41 cocktail:

  1. Fioricet 1 q4h
  2. tramadol 100 q6h
  3. valproate 500 IV q8h x3d
  4. metoclopramide 5-10mg q6h x 3d
  5. Mg 2G IV once

*monitor QT interval

 

References

Dorhout Mees, S., Bertens, D., van der Worp, H., Rinkel, G., & van den Bergh, W. (2009). Magnesium and headache after aneurysmal subarachnoid haemorrhage. Journal Of Neurology, Neurosurgery & Psychiatry81(5), 490-493. doi: 10.1136/jnnp.2009.181404

Swope, R., Glover, K., Gokun, Y., Fraser, J., & Cook, A. (2014). Evaluation of headache severity after aneurysmal subarachnoid hemorrhage. Interdisciplinary Neurosurgery1(4), 119-122. doi: 10.1016/j.inat.2014.07.003

Central Fever

Central fever / Paroxysmal Hyperthermic Autonomic Dysregulation

  • commonly associated with closed head injury, hydrocephalus
  • nonsustained episodes of hyperpyrexia, tachycardia , tachypnea, increased blood pressure, increased extensor tone, pupil dilatation, diaphoresis (see related post on sympathetic storming)

Pathophysiology:

  • injury involving hypothalamus
  • neuroimmulogic mechanisms?
  • initial release of cytokines (IL-1, IL-6, TNF-α and IFN-γ), secondary to direct trauma, infection of brain, inflammatory stimulation and increased ICP after acute brian injury activate COX-2 pathways in periventricular cells and production of PGE
  • stressed cells after brain injury synthesize heath shock proteins in coordinated response to tissue injury
  • glutamate and nitric oxide release caused by autonomic dysregulation of the brianstem

Rule out:

  • infection
  • epileptic disorders
  • pheochromocytoma
  • NMS
  • increased ICP
  • hydrocephalus
  • Cushing’s syndrome
  • thyrotoxicosis
  • DVT

Treatment:

  • The current effective drugs are
    • propranolol, opioid, clonidine, bromocriptine, chlorpromazine, dantrolene  
    • Propranolol 20 to 30 mg every 6 hours
  • Stereotactic surgery is sometimes considered when these drugs are ineffective

 

Reference:

Meythaler, J., & Stinson, A. (1994). Fever of central origin in traumatic brain injury controlled with propranolol. Archives Of Physical Medicine And Rehabilitation75(7), 816-818. doi: 10.1016/0003-9993(94)90143-0

Oh, S., Hong, Y., & Song, E. (2007). Paroxysmal Autonomic Dysregulation with Fever that was Controlled by Propranolol in a Brain Neoplasm Patient. The Korean Journal Of Internal Medicine22(1), 51. doi: 10.3904/kjim.2007.22.1.51

 

 

Recommendations for Thromboprophylaxis in Hospitalized COVID Patients

321

 

Hospitalized COVID AC Recs.May2020

Reference:

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

Diagnostic Tests for SARS-CoV2

DETECTION OF VIRAL RNA (RT-PCR tests)

  1. RT PCR targets the following genes
    1. env – envelope
    2. N – nucleocapsid
    3. S – spike
    4. RdRp – RNA-dependent RNA polymerase
    5. ORF1 genes
  2. Cycle threshold
    1. number of replication cycles required to produced a fluorescent signal
    2. lower Ct values represent higher viral RNA loads
    3. Ct value <40 clinically reported as PCR positive
    4. Ct values in severely ill patients are lower than mild cases
  3. (+) PCR result reflects only detection of the viral RNA, not necessarily indicate presence of viable virus
  4. Sn/Sp
    1. RT-PCR positivity
      1. BAL specimen (93%)
      2. sputum (72%)
      3. nasal swab (63%)
      4. pharyngeal swab (32%)
    2. Specificity is 100%

nejmp030078_f1

DETECTION OF ANTIBODIES

  1. most sensitive and earliest serological maker is TOTAL ANTIBODIES, which increase from 2nd week of symptom onset
  2. IgM and IgG ELISA have been found (+) as early as Day 4 of symptom onset
    1. higher levels in second and third week
    2. IgG and IgM seroconversion occurred in all patients between third and fourth week
    3. IgM begins to decline and reach lower levels by week 5 and disappears by week 7
    4. IgG persists beyond 7 weeks
  3. >95% specificity for diagnosis of COVID-19
  4. Sn/Sp
    1. majority of Ab are produced against NC (most abundant protein of the virus), tests to detect Ab would be most sensitive
    2. receptor-binding domain of S (RBD-S) protein is the host attachment protein, would be more specific and expected to be neutralizing

References:

Sethuraman, N., Jeremiah, S., & Ryo, A. (2020). Interpreting Diagnostic Tests for SARS-CoV-2. JAMA. doi: 10.1001/jama.2020.8259

Holmes, K. (2003). SARS-Associated Coronavirus. New England Journal Of Medicine348(20), 1948-1951. doi: 10.1056/nejmp030078

Unruptured Intracranial Aneurysm Treatment Score

UIATS = Unruptured Intracranial Aneurysm Treatment Score

  • quantifies 29 key factors related to patient, aneurysm and treatment characteristics involved in clinical decision-making in management of unruptured aneurysm
  • 2 scores generated – 1 favoring repair and the other favoring conservative management.
  • For a score difference with >3 points, higher score suggests the type of treatment
  • For a score difference with <=2 points, no definitive recommendations can be made

 

 

Reference:

Mayer, T., Etminan, N., Morita, A., & Juvela, S. (2016). The unruptured intracranial aneurysm treatment score: A multidisciplinary consensusAuthor Response. Neurology86(8), 792.2-793. doi: 10.1212/01.wnl.0000481228.68055.71