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.

Hyponatremia Protocol

Na <133 mEq/L or a decrease of 6 mEq/L in 24 to 48 hours:

  1. NaCl tabs 3 g PO/NGT q6h
  2. Start 3%NaCl at 20 mL/h
  3. BMP q6h

Na <130:
Increase rate by 20 mL/h (max rate = 80 mL/h)
If on hold at present, initiate 3 percent NaCl infusion at 20 mL/h IV

Na = 130-135:
Increase rate by 10 mL/h (max rate = 80 mL/h)
If on hold at present, initiate 3 percent NaCl infusion at 10 mL/h IV

Na = 136-140:
No change

Na ≥140:
Hold infusion



Woo, Carolyn H. et al. “Performance Characteristics Of A Sliding-Scale Hypertonic Saline Infusion Protocol For The Treatment Of Acute Neurologic Hyponatremia”. Neurocritical Care 11.2 (2009): 228-234. Web.

The Latest on DOACs (reversal and other important stuff to know)


DOACs target specific enzymes in the common pathway of coagulation cascade.  (vs warfarin which attenuates thrombin generation by decreasing levels of factors 2, 7, 9, 10).

Dabigatran has high affinity for thrombin, inactivates fibrin-bound as well as unbound thrombin, preventing conversion of fibrinogen to fibrin.

Rivaroxaban, apixaban and edoxaban directly inhibits free and clot-bound factor Xa without requiring cofactors, and suppress synthesis of new plasma thrombin but has no effects on the activity of existing thrombin.

Nonspecific Reversal Agents:

  1. Activated charcoal
    1. For acute intoxication (dabigatran studies) within 1-2h after intake of drug
    2. Efficacy not tested in clinical practice
  2. DDAVP
    1. Stimulates release of factor VIII and vWF from vascular endothelium
    2. One study (healthy volunteers), DDAVP infusion causes significant dose-dependent reduction in hirudin, induced prolongation of aPTT in vivo
    3. No clinical trials in bleeding patients on DTI
  3. PCCs (inactive)
    1. Inconsistent results
  4. PCCs (activated)
    1. Given at a dose of 50 or 100 IU/Kg reduces bleeding time in dabigatran-treated animal model
    2. Ex vivo study showed reversing impaired thrombin generation in healthy individuals treated with dabigatran
    3. Most reasonable alternative for reversing dabigatran (until recently) but weigh risk-benefit because of associated increased risk of thromboembolic complications
  5. rFVIIa
    1. no trial conducted to prove effect on reversal of dabigatran
    2. 4 case reports showed ineffective in dabigatran-induced bleeding in 3 patients
  6. Dialysis
    1. Low plasma protein binding (35%), so dabigatran can be dialysed in case of overdose, life-threatening bleeding or before emergency surgical situation
    2. Difficulty with establishing access in bleeding patient


Summary of DOACs:






Idarucizumab is a humanized monoclonal Ab fragment (Fab) that binds free and thrombin-bound dabigatran.  Kidneys eliminate idarucizumab-dabigatran complex.  Idarucizumab binds to dabigatran with affinity 350x higher than binding affinity of dabigatran for thrombin.

Andexanet is a recombindnant modified human factor Xa decoy protein.  It binds to Factor Xa inhibitors in their active site with high affinity.  It binds and removes Factor Xa inhibitors.  This is assessed by measurement of thrombin generation and anti-factor Xa activity.

Aripazine PER977 binds specifically to UFH and LMWH through noncovalent H bonding and charge-charge-interactions.  It binds in a similar way to all 4 DOACs.  This drug reverses anticoagulant activity in ex-vivo human studies through aPTT and anti-Xa analysis.






Idarucizumab and ANNEXA studies:



Tummala, Ramyashree et al. “Specific Antidotes Against Direct Oral Anticoagulants: A Comprehensive Review Of Clinical Trials Data”. International Journal of Cardiology 214 (2016): 292-298. Web.

Serratia marcescens

Serratia marcescens

  • anaerobic GNR, family Enterobacter
  • associated with hospital-onset infections
  • intrinsically resistant to ampicillin, amoxicillin, ampisulbactam, amoxiclav,, narrow-spectrum cephalosporins, cefuroxime,/ macrolides, tetracytclines, nitrofurantin and colistin
  • potential to harbor MDR mechanisms (AmpC or ESBL and carbapenemases)


  • uncomplicated infection – FQ, TMP SMZ, zosyn, ceph3 or ceph4, carbapenems
  • risk of AmpC-mediated resistance during therapy
    • likely with CNS infections, infections in sequestered sites that require prolonged antibiotic therapy, retained infected material
    • do not use ceph3 even if susceptible
    • in CNS infections – favor carbapenem or cefepime
    • other sequestered sites  FQ and TMP-SMZ
  • high level expression of AmpC beta-lactamase or ESBL – carbapenem

Duration of therapy 

  • depends on site of infection and clinical response
  • repeat culture/susceptibility testing and adjust Rx accordingly



Uptodate.  Serratia marcescens. Accessed 03/15/2016.

Valproic Acid Toxicity


(with permission from Dr. Valerie Demekhin to repost)


VPA is well absorbed from the GI tract with bioavailability of 80 – 90%. Peak concentrations are usually reached in 6 hours (except for enteric coated Depakote DR/ER formulations which peak in up to 24 hours). VPA is 90% protein bound at therapeutic concentrations, but the percentage decreases to up to 35% as the VPA concentration exceeds 300 mg/L due to saturation of binding sites.

Less than 3% of valproic acid is excreted in urine (we do not worry about renal adjustment or accumulation regardless of renal function) but the drug undergoes extensive liver metabolism.

Hepatic metabolism is complex and utilizes the same enzymes as mitochondrial lipid metabolism. Glucuronidation, mitochondrial ß- oxidation, and cytosolic ω- oxidation account for 50%, 40%, and 10% respectively of VPA. ß- oxidation occurs in mitochondrial matrix and starts with passive diffusion of VPA across mitochondrial membrane and ends with transport of metabolites in opposite directions using acetylCoA and carnitine as transporters.

ß- oxidation of VPA depletes carnitine stores; VPA metabolites trap mitochondrial CoA that leads to decreased ATP production (negatively affects carnitine transporters). Depletion of carnitine and the limited pool of free CoA lead to excessive ß- oxidation and ultimately to hyperammonemia (CPS I excess).

Electrolytes, blood gases, liver function tests, platelets, and serum lactate and serum ammonia concentrations should be monitored in all patients. Hyperammonemia (>80 μg/dL or >35 μmol/L) occurs in up to 80% of patients receiving chronic VPA therapy.

Management of VPA toxicity includes supportive management and discontinuation of therapy. Carnitine should be administered in the event of hyperammonemia or hepatotoxicity. IV carnitine is preferred in symptomatic patients, while oral carnitine is sufficient asymptomatic patients. The LD is 100 mg/kg over 30 minutes followed by 15 mg/kg over 10 – 30 minutes every 4 hours until clinical improvement occurs. However, it is important to acknowledge that the recommendations are based on toxicology emergency cases where doses ingested and the levels are far above what we see in the hospital. The indications for treatment are usually hyperammonemia, lethargy, coma or hepatic dysfunction. For patients with acute overdose but without clinical findings of toxicity, oral carnitine can be administered with a dose of 100 mg/kg day (up to 3 grams) divided every 6 hours.

Oral carnitine reverses carnitine deficiency and results in resolution of ammonia levels and improves lethargy in chronically treated VPA patients. Unanswered questions are the duration of L-carnitine supplementation and the effect of its administration on the VPA level.



  1. Goldfrank, Doyon, Toxicologic emergencies. Chapter 48: antiepileptics. 10th
  2. Howland MA. L-Carnitine. In: Goldfrank’s Toxicological Emergencies, 9th, McGraw Hill Medical, New York 2011. p.711.
  3. Ohtani, Carnitine deficiency and hyperammonemia with valproic acid therapy. J Pediatr 1982;101(5):782.
  4. Gidal Diet and valproate induced transient hyperammonemia: affect of L-carnitine. Pediatr Neurol 1997;16(4):301.
  5. Jackie Raskind, The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000;34:630-8.a


Valerie Demekhin, Pharm.D., BCPS
Dr. Demekhin participates in multidisciplinary patient care rounds and provides pharmacotherapy services in the neurosurgery, neurology and epilepsy care unit. Dr. Demekhin precepts PGY-1 pharmacy residents for the neurology/neurosurgery rotation. In addition, she is a member of stroke and neurology committees. Dr. Demekhin is an active member within American College of Clinical Pharmacy (ACCP), Society of Critical Care Medicine (SCCM), American Society of Health System Pharmacists (ASHP), New York City Society of Health-System Pharmacists (NYSCHP) and Royal Counties Society of Health System Pharmacists (RCHSP). She serves as a journal review for Journal of Pharmacy Practice and has presented on topics such as pulmonary arterial hypertension, management of toxicological emergencies (calcium channel and beta blockers overdose, role of lipids in toxicology world, sulfonylurea overdose,, management of hypertensive urgencies and emergencies, therapeutic hypothermia, sepsis and stroke.

Dr. Demekhin’s areas of interest include toxicology, sedation, infectious diseases, stroke, and surgery/neurosurgery.




Additional Notes:

Hyperammonemia/encephalopathy: Hyperammonemia and/or encephalopathy, sometimes fatal, has been reported following the initiation of valproate therapy and may be present with normal transaminase levels.

Ammonia levels should be measured in patients who

  1. develop unexplained lethargy and vomiting, or
  2. develop changes in mental status or
  3. present with hypothermia.


Discontinue therapy if ammonia levels are increased and evaluate for possible urea cycle disorder (UCD). Hyperammonemic encephalopathy has been reported in patients with UCD, particularly ornithine transcarbamylase deficiency. Use is contraindicated in patients with known UCD.

Evaluation of UCD should be considered for the following patients prior to the start of therapy:

  • History of unexplained encephalopathy or coma;
  • encephalopathy associated with protein load;
  • pregnancy or postpartum encephalopathy;
  • unexplained mental retardation;
  • history of elevated plasma ammonia or glutamine;
  • history of cyclical vomiting and lethargy;
  • episodic extreme irritability, ataxia;
  • low BUN or protein avoidance;
  • family history of UCD or unexplained infant deaths (particularly male); or
  • signs or symptoms of UCD (hyperammonemia, encephalopathy, respiratory alkalosis).

Hyperammonemia and/or encephalopathy may also occur with concomitant topiramate therapy in patients who previously tolerated monotherapy with either medication.



Empirical Antimicrobial Therapy for Adult Patients with Presumed Bacterial Meningitis


* Ceftriaxone or cefotaxime.    Cefepime, ceftazidime.


Infection Empiric treatment
Meningitis–Community associated Dexamethasone 0.15 mg/kg IV every 6 h if pneumococcal meningitis suspected

Before or concomitantly with

Vancomycin dosed to goal trough 15–20 mcg/mL


Ceftriaxone 2 g IV every 12 h

If over age 50, pregnant or immune compromised

Add Ampicillin 2 g IV every 4 h

If herpes meningoencephalitis suspected

Add Acyclovir 10 mg/kg IV every 8 h


Textbook of Critical Care, Sixth Edition. Vincent, Jean-Louis, MD, PhD.

O’Horo, J. and Sampathkumar, P. (2017). Infections in Neurocritical Care. Neurocritical Care.

ENLS 2017 Pharmacotherapy.  Neurocritical Care Journal.