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

Phenytoin Drug Monitoring

After loading dose

  • First concentration: draw within 2-3 days
    • if rapid therapeutic levels needed, draw 2 hours after IV loading dose or 24 hours after oral loading dose to determine maintenance dose or need to reload
  • Second concentration: draw within 5-8 days of therapy initiation with subsequent doses of phenytoin adjusted accordingly
  • if levels unchanged over 3-5 days, monitor once a week (acute clinical setting).
  • stable / long-term therapy, monitor every 3-12 months

 

Corrected for Low Albumin:

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Corrected for Renal Failure (CrCl <10):

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REFERENCE:

Uptodate: Phenytoin: Drug information.  Accessed 04/25/2020.

Stress Dose Steroids

WHEN IS STRESS DOSE STEROIDS INDICATED?

  • depends on history of steroid intake and likelihood of HPA supression + type and duration of surgery
  • NONSUPPRESSED HPA AXIS: 
    • < 3 weeks of steroids at any dose
    • prednisone <5mg/daily for any duration
    • prednisone <10mg every other day
    • PLAN:  continue same regimen perioperatively; no need for cosyntropin test or stress dose steroids
  • SUPPRESSED HPA AXIS
    • prednisone >20mg/day x 3 weeks or more OR Cushingoid appearance
    • PLAN:
      • give stress dose steroids based on type and duration of surgery (see below)
  • INTERMEDIATE HPA SUPPRESSION (Unknown HPA Axis suppression, previous 3 or more intraarticular or spinal steroid injections within 3 mos prior to suregery)
    • PLAN
      • evaluate HPA axis 
        • check AM cortisol (8a.m.) after 24h off steroids
        • if <5 ug/dL – likely suppressed axis; give stress dose steroids
        • if >10 ug/dL – likely no supression; continue current dose on day of surgery
        • if 5-10 ug/dL – ACTH stim test or empiric stress dose steroids
      • ACTH stim test (standard is 250 ug):
        • if serum cortisol <18 ug/dL 30 mins after ACTH – give stress dose steroids
        • if >serum cortisol >18 ug/dL 30 mins after ACTH – no stress dose steroids

 

STEROIDS BASED ON TYPE AND DURATION OF SURGERY

MINOR PROCEDURES / LOCAL ANESTHESIA – stress dose not necessary, take AM steroids

MODERATE SURGICAL STRESS: (eg. LE revascularization, total joint replacement)

  1. take AM steroids
  2. hydrocortisone 50mg IV prior to procedure, 25mg IV q8h x 24h
  3. resums usual dose after

MAJOR SURGICAL STRESS (e.g open heart surgery, proctocolectomy, esophagogastrectomy)

  1. take AM steroids
  2. hydrocortisone 100mg IV before induction of anesthesia
  3. hydrocortisone 50mg q8h x 24h
  4. taper by half per day to maintenance dose

 

 

 

Reference:

Uptodate.com. (2018). UpToDate. [online] Available at: http://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids?search=stress+dose+steroids&source=search_result&selectedTitle=1~60#H6 [Accessed 25 Mar. 2018].

Treatment of Native Vertebral Osteomyelitis (IDSA, 2015)

Parenteral Antimicrobial Treatment of Common Microorganisms Causing Native Vertebral Osteomyelitis

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Reference:

Berbari, Elie F. et al. “2015 Infectious Diseases Society Of America (IDSA) Clinical Practice Guidelines For The Diagnosis And Treatment Of Native Vertebral Osteomyelitis In Adults”. Clinical Infectious Diseases 61.6 (2015): e26-e46. <PDF link>

 

Sulfa Allergy

Drugs to avoid in patients with sulfonamide allergy:

Antimicrobials

  • Sulfamethoxazole
  • Sulfamerazine
  • Sulfamethizole
  • Sulfamoxole
  • Sulfamethazine
  • Sulfoxazole
  • Sulfapyridine

Nonantimicrobials (diuretics, triptans, oral hyopglycemics, antiinflammatories)

  • Bumetanide
  • Furosemide
  • Celecoxib
  • Acetazolamide
  • Sumatriptan
  • Hydrochlorothiazide Diazoxide
  • Glyburide
  • Sulfasalazine

 

Reference:

 

Uptodate.  “Sulfonamide allergy in HIV-uninfected patients.” Accessed 03/13/2017.

Medications Used to Treat Seizures and Status Epilepticus in Adult ICU Patients

AEDs in the ICU.

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1b

1c

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From ENLS:


Mechanism of action

  1. Benzodiazepines – stimulates GABA A receptor subunits, leads to inhibition of transmission through chloride channel-induced hyperpolorization of resting cells embrane, at high levels Benoza function in a manner similar to phenytoin

 

Neurocritical Care Society provided dosing cards for IV and PO AEDs in their website for free.  See links below for PDF files.

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NCS_287285-18_Dosing_Cards1_r2

NCS_287285-18_Dosing_Cards2_r2

Reference:

Tesoro, Eljim P. and Gretchen M. Brophy. “Pharmacological Management Of Seizures And Status Epilepticus In Critically Ill Patients”. Journal of Pharmacy Practice 23.5 (2010): 441-454. Web.

Manno, in The Neurohospitalist

Medication Dosing Cards | NCS. (2019). Retrieved from https://www.pathlms.com/ncs-ondemand/courses/2653/sections/12865