ANDEXANET ALFA Guidelines

Andexanet alfa works as a decoy drug for Factor Xa inhibitors in the blood, and prevents drug inhibition of native Factor Xa.

INDICATIONS:  apixaban / rivaroxaban exposure w/in 24h of life-threatening bleed:

  • acute intracranial hemorrhage (approval from stroke neurologist / neurointensivist / neurosurgeon)
  • spinal or epidural hemorrhage (approval from site medical director)
  • intraocular hemorrhage with vision compromise (approval from site medical director)
  • airway or pulmonary hemorrhage (approval from site medical director)
  • hemopericardium (approval from site medical director)
  • aortic rupture, dissection or hemorrhage (approval from site medical director)
  • closed space hemorrhage – compartment syndrome risk (approval from site medical director)

*Not indicated for bleeding from all other sites.

DOSAGE:

Capture

Capture2

(1 vial  = 200mg = 20 mL)

Precautions:

  1. thrombotic events
  2. incomplete reversal
  3. Anti-FXa levels return to placebo levels ~12h after complution of bolus or infusion.
  4. interferes with indirect anti-Xa inhibitors (UFH)
  5. infusion related-reactions in 18% of healthy volunteers

Note: DO NOT co-administer andexanet and Kcentra.

Note:  Andexanet has not been studied in patients requiring reversal prior to urgent or emergent surgery – concern for rebound bleeding / hypercoagulability, unpredictable pharmacokinetics, lack of data in surgical population.  PCCs have been studied in the surgical population.

Infusion Reactions:

  • fever, rigors, severe chills
  • hypertension
  • oxygen desaturation
  • agitation / confusion
  • flushing, feeling hot
  • cough
  • dysgeusia
  • dyspnea

 

 

Does impaired venous drainage worsen cerebral edema in acute ICH?

Here is an interesting study from Zhejiang University School of Medicine that explored the relationship between cerebral venous drainage and the development of perihematomal edema after ICH.

The authors reviewed 138 patients with ICH who underwent CTP and noted the presence or absence of filling of the following veins:

  • superficial middle cerebral vein
  • Vein of Trolard
  • Vein of Labbe
  • Basal vein of Rosenthal
  • Internal cerebral Vein

AIVF, or absent ipsilateral venous filling, was documented and correlated with perihematomal edema formation on follow-up CT.

The study found that AIVF occurred in about 1/3 of patients with acute ICH and was strongly related to the development of PHE.

Examples of how veins were identified with the CTP:

  • *red arrow – presence of vein
  • *red circle – absent filling of vein

Enlarged images below:

Study showed that AIVF was independently associated with larger perihematomal edema at 24 hours.

Implications of this research: May provide potential therapeutic targets to prevent edema progression – (s.a. ?respiratory adjustments to affect jugular pressure or cerebral capillary perfusion; ?adequate volume expansion).

Reference:

Chen, L., Xu, M., Yan, S., Luo, Z., Tong, L. and Lou, M. (2019). Insufficient cerebral venous drainage predicts early edema in acute intracerebral hemorrhage. Neurology, pp.10.1212/WNL.0000000000008242.

Post-operative Ophthalmoplegia (after transphenoidal surgery)

Causes of post-operative ophthalmoplegia:

  • Compressive post-operative hematoma
  • Minimal intrasellar and intracavernous interstitial hemorrhage
  • Intracavernous residual tumor
  • Rare – iatrogenic pseudoaneurysm
  • Rare – traumatic intraoperative lesion

Extraocular nerve palsy mainly involves CNs III and VI, probably related to anatomical disposition into the cavernous sinus, whereas CN IV palsy rare. (CN6 > CN3 > CN4)

CASE #1. CN 3 palsy 24 hours after surgery of Knosp grade 2 gonadotropic daemons. Post-op CT shows a hematoma. Patient underwent re-operation with complete recovery 3 days after decompression.

CASE #2. CN VI palsy 36 hours post-op (acromegaly, microadenoma L anterior pituitary). Post-op CT shows L cavernous sinus slightly hyper dense, suggesting minimal hemorrhagic suffusion into cavernous sinus. No reoperation, recovered over 3 months.

Most probably cause for transient complication is a hemorrhagic suffusion in the cavernous sinus during surgery and in the hours following the procedure, generating a swelling process that affects the intracavernous nerves in the first days after surgery. Because no direct nerve damage occurred, defici recovers as the swelling resolves.

CASE #3. L palpebral pros is and myriad is 48h after surgery of Knosp grade 4 non functioning adenoma. Post-op CT shows residual tumor in L cavernous sinus. No reiteration indicated, complete recovery by 3 months.

Partial resection of the cavernous extension of the adenoma leads to post-operative swelling of the residual tumor.

Clinical Pearl. Extraocular deficit present immediately after surgery is likely related to a direct lesion of the nerve, and more likely to remain permanent, while appearance of ophthalmoplegia with a delay of 12-72 hours post-operatively is likely due to a swelling process, and is, in almost all cases, completely resolved within the 3 months after surgery.

Reference:

Florea, S., Graillon, T., Cuny, T., Gras, R., Brue, T. and Dufour, H. (2019). Ophthalmoplegic complications in transsphenoidal pituitary surgery. Journal of Neurosurgery, pp.1-9.

DIDVI – Diapetes Insipidus after Discontinuation of Vasopressin Infusion

Mechanism:

  1. Shock, vasoplegia (hypotension, low SVR in the presence of normal CO)
  1. Treatment with supraphysiologic doses of vasopressin*
  1. Downregulation of V2 receptors
  1. Vasopressin discontinued
  1. Polyuria + hypernatremia (DIDVI)
  1. Expression of new V2 receptors
  1. Back to normal

*typically, vasopressin is administered at 0.03 to 0.04 U/min in septic shock, but is approved and often used at doses up to 0.1 U/min in post cardio tiny shock.

Figure below shows serum levels of a patient after multiple discontinuations of vasopressin infusion.

Management of DIDVI:

  • Resumption of vasopressin promptly corrects the disorder
  • In some patients, twice daily IV or SQ decompression may be adeqaute

Reference:

Ferenchick, H., Cemalovic, N., Ferguson, N. and Dicpinigaitis, P. (2019). Diabetes Insipidus After Discontinuation of Vasopressin Infusion for Treatment of Shock. Critical Care Medicine, p.1.

RAGS score for AVM

RAGS stands for The Ruptured AVM Grading Scale. The RAGS score aims to predict clínical outcome after AVM rupture. It includes the Hunt and Hess score, age, +/- deep venous drainage and eloquent location of the AVM. RAGS score is an extension of the familiar HH scale that makes it specific to AVMs and is more accurate at predicting clinical outcome than existing grading systems.

Reference:

Silva, M., Lai, P., Du, R., Aziz-Sultan, M. and Patel, N. (2019). The Ruptured Arteriovenous Malformation Grading Scale (RAGS): An Extension of the Hunt and Hess Scale to Predict Clinical Outcome for Patients With Ruptured Brain Arteriovenous Malformations. Neurosurgery.

SwICH Score: The Surgical Swedish ICH Score

30-day Mortality Rates with SwICH Score:

Comparing SwICH with the original ICH score:

Take Home:

  • SwICH score is the first clinical grading scale for patients with ICH who were treated surgically.
  • Cohort limited to supratentorial ICHs.
  • Intraventricular extension and hydrocephalus were not independent predictors of 30-day mortality.
  • Two additional independent predictors of 30-day mortality were found – DM and h/o MI.
  • Needs external validation to assess generalizability and predictive value.

Reference:

Fahlström, A., Nittby Redebrandt, H., Zeberg, H., Bartek, J., Bartley, A., Tobieson, L., Erkki, M., Hessington, A., Troberg, E., Mirza, S., Tsitsopoulos, P. and Marklund, N. (2019). A grading scale for surgically treated patients with spontaneous supratentorial intracerebral hemorrhage: the Surgical Swedish ICH Score. Journal of Neurosurgery, pp.1-8.

Cannabinoids

Important cannabinoids:

Mechanism of Action:

Modulation of the endocannabinoid system by phytocannabinoids.

Figure illustrates basic actions of endogenous cannabinoids anandamide (AN) and 2-arachidonylglycerol (2-AG) on the G protein-coupled cannabinoid receptors 1 and 2 (CB1 and CB2) in presynaptic neurons in both the central and peripheral nervous system.

Green-shaded compounds are common phytocannabinoids and other herbal inclusions in hemp oils that affect normal endocannabinoid through modulation of the CB receptors (eg, THC agonism of CB1 receptors) or by other routes s.a. inhibition of enzymatic breakdown of endocannabinoids or other receptor modulation.

BCP = Beta caryophyllene

GABA = gamma-aminobutyric acid

TRPV = transient receptor potential vanilloid

Figure below lists the current laws regarding CBD oils and medical marijuana in the US. For most up to date information, see website from National Conference of State Legislatures.

Federal government and DEA still consider CBD and hemp oils to be schedule I substances. DEA recently reduced Epidiolex (pure CBD drug recently FDA_approved) to schedule V classification.

Epidiolex is approved for:

  • Intractable epilepsy conditions
  • Dravet syndrome
  • Lennox-Gastaut syndrome

Reference:

VanDolah, H., Bauer, B. and Mauck, K. (2019). Clinicians’ Guide to Cannabidiol and Hemp Oils. Mayo Clinic Proceedings, 94(9), pp.1840-1851.