Anticoagulation Reversal Agents

Reversal Agents (click to access pdf)

Reference:

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf accessed 12/30/2015 7:09 a.m.

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf

http://geiselmed.dartmouth.edu/radiology/pdf/Anticoag%20Holding%20Recs.pdf

AED Therapeutic Drug Levels

The concept of critical values for drug levels was originally developed by the late Daniel M. Baer, MD, and first published in the April 1982 issue of MLO. This table was taken from an expanded version of that publication and newly revised for 2011-2012 by Yashpal Agrawal, MD, PhD; Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Cornell Campus, New York, NY.

therapeutic drug levels.jpg

Imaging in Vasogenic Edema

Pathophysiology:  disturbance of vascular permeability –> plasma fluid and protein escapes –> increase in extracellular space volume

  • Vasogenic edeme represents reactive changes rather than permanent cell damage, and are therefore reversible.

Peritumoral edema:  nonenhancing area of abnormality surrounding enhancing tumor core

  • mets or noninfiltrative primary tumors (meningiomas) – peritumoral edema is synonymous with vasogenic edema (no tumor cells are present)
  • Gliomas – peritumoral edema better referred to as infiltrative edema because it represents both vasogenic edema and infiltrating tumor cells behing the BBB and invading the white matter tracts

CT Scan:

  • brain tumors identified by abnormal density +/- distortion of adjacent structures
  • tumor-induced vasogenic edema extends along white matter extracellular fluid spaces and appear hypodense
  • contrast enhancement: defines the tumor border (if tumor is contrast enhancing)

F5.small
Noncontrast CT showing vasogenic edema surrounding a brain tumor.

MRI:

  • T1-weighted with contrast – edema may be subtle
  • T2-weighted – edema readily apparent
  • FLAIR – CSF signal suppressed to make lesions adjacent to ventricles more conspicuous
  • DWI – differentiates cytotoxic edema from vasogenic edema

F6.large.jpegA = noncontrast T1W;  B = T1W with contrast; C=T2W; D= FLAIR

 

References

Esquenazi, Y., V. P. Lo, and K. Lee. “Critical Care Management Of Cerebral Edema In Brain Tumors”.Journal of Intensive Care Medicine (2015): n. pag. Web.

Herniation Syndromes

Types of Herniation

  1. Subfalcine herniation
    • supratentorial mass lesions may lead to cingulate gyrus hernation
    • often in supratentorial metastasis, low- or high-grade gliomas
    • pericallosal branches of ACA along free edge of falx may be compressed leading to infarction
  2. Uncal herniation
    • most common type
    • presents as: impaired consciousness, fixed dilated ipsilateral pupil, hemiparesis contralaterally
    • uncus herniates over tentorial edge, compresses CN III
    • uncus can also herniate into midbrain and into posterior fossa, compressing corticospinal tract
    • PCA may be compressed between uncus and midbrain causing occipital lobe infarct
  3. Central herniation
    • generalized cerebral mass effect
    • entire mid-brain herniates downward
    • presentation: obtunded with altered breathing pattern, pinpoint pupils, loss of upward gaze
  4. Tonsillar herniation:
    • infratentorial tumors cause cerebellum to herniate through foramen magnum compressing the medulla
    • presentation:  cardiorespiratory dysfunction, altered breathing patterns, impaired consciousness

Treatment:

  1. positioning:  elevate head 30° (decrease CSF hydrostatic pressure, facilitate venous drainage), head facing straightforward (decrese IJ vein compression), remove constricting garments or devices around neck
  2. avoid hypoxia and hypercapnia – target PaCO2 35-40 mm Hg, intubate if declining neurologic status or GCS <8 or requiring sedation / GA for ICP control
  3. hemodynamic support – maintain euvolemia (use isotonic fluids); avoid CPP<50mm Hg; initiate treatment if CPP fall <60 to avoid CPP<50mm Hg; vasopressors, avoid vasodilators (nitroglycerine and nitroprusside – exacerbates cerebral edema through cerebral hyperemia)
  4. avoid fever, hypothermia may be effective in lowering ICP but long-term outcome still unclear; target normothermia for now
  5. anticonvulsants – seizures affect airway, increases PaCO2, exacerbates cerebral edema and ICP; seizure prophylaxis after crani for tumor resection still unclear but prudent to start prophylaxis for supratentorial brain tumors; prefer newer generation anticonvulsants
  6. Mannitol 25% at 0.5-1.5 g/Kg – reduces ICP, peak effect 15-35 mins after infusion, duration several hours; osmotic diuresis may lead to hypovolemia and electrolyte imbalance (check q6-8h); given peripheral or through central IV catheter over 10-20minutes;  high osmotic levels may produce renal damage; upper limit to safely administer mannitol is 320 mOsm/L; may leak into brain parenchyma and exacerbate vasogenic edema if used over sustained time
  7. hypertonic saline – continuous infusion (2-3%) or bolus (23.4%); central venous catheter needed for concentrations 3% or higher; complications include fluid overload (CHF); do not abruptly stop infusion to avoid rebound ICP; wean over 12-24h
  8. Steroids – reduces permeability of tumor capillaries, dexamethasone is drug of choice (low index of Na and water retention, long half life, low mineralocorticoid activity, low tendency to induce psychosis, controls tumor-associated pain, limits n/v, improves appetite in cancer); 10-20mg IV x1 if with acute nruologic symptoms, maintenance dose of oral or IV 4-24mg in divided doses; expect improvement in 48 hours, use lowest effective dose; use GI prophylaxis
  9. Surgery – resection, intraventricular catheterization

Future Therapies

  1. inhibition of VEGF – SU5416 (semaxanib), AZD2171
  2. COX-2 inhibitors – inhibits production of prostaglandins involved in inducing cerebral edema, also found to induce apoptosis and prevent anigogenesis; SC-236, rofecoxib, PPAR-γ

 

References

Esquenazi, Y., V. P. Lo, and K. Lee. “Critical Care Management Of Cerebral Edema In Brain Tumors”.Journal of Intensive Care Medicine (2015): n. pag. Web.

Reversal of Factor Xa Inhibitors (The 2 ANNEXA Trials)

This blog reviews the article published in NEJM this week about the results of the ANNEXA trials.  ANNEXA stands for Andexanet Alfa – a Novel Antidote to the Anticoagulant Effects of FXA Inhibitors.  The study has two arms – ANNEXA-A and ANNEXA-R that looked into reversal of apixaban and rivaroxaban, respecively.

The study enrolled a small cohort of healthy older volunteers, who received either Rivaroxaban 20mg PO OD x 4 days, or Apixaban 5mg PO BID x 3.5 days to achieve steady state levels of the drug.  These volunteers were given the reversal agent Andexanet as a bolus or a bolus and infusion, or placebo.

  • ANNEXA-R:  800mg IV bolus (30mg/min) or 800mg IV bolus + 8mg/min x 2 hours [960mg total)
  • ANNEXA-A:  400mg IV bolus (30mg/min) or 400mg IV bolus + 4mg/min x 2 hours [480mg total)

The study showed that anti-factor Xa activity was reduced within 2-5 minutes, which persisted for 2 hours after administration of the drug. Thrombin generation was also demonstrated to be rapidly restored within 2-5 minutes of drug administration.

 

Mechanism of Action:  Andexanet is a recombinant modified human factor Xa decoy protein.  It is a catalytically inactive protein but is able to bind factor Xa inhibitors in the active site with high affinity.  The drug also binds and sequesters factor Xa inhibitors within the blood vessel, reducing the serum levels and reversing the effects of the anticoagulant.

Capture2

 

 

References

Siegal, Deborah M. et al. “Andexanet Alfa For The Reversal Of Factor Xa Inhibitor Activity”. New England Journal of Medicine 373.25 (2015): 2413-2424. Web.

The New England Journal of Medicine,. The ANNEXA-A And ANNEXA-R Trials.. 2015. Web. 20 Dec. 2015.

Treatment of Vasogenic Edema

Pathogenesis:  production of VEGF, glutamate, leukotrienes (increases permeability of tumor vessels) and absence of tight endothelial cell junctions in tumor blood vessels (respond to VEGF and basic fibroblast growth factor)
 Presentation1
Gliomas, meningiomas, metastatic tumors –> secretes VEGF –> binds to VEGFR1 and VEGFR2 (surface of endothelial cells –> formation of gaps in endothelium –> fluid leakage into brain parenchyma –> vasogenic edema –> spreads more in white matter (lower resistance than gray matter) –>  disrupts synaptic transmission, alters neuronal excitability –> HA, seizures, focal deficits, encephalopathy, herniation
DEXAMETHASONE
Advantages:  Lack of mineralocorticoid activity, less fluid retention; lower risk of infection and cognitive impairment
Mechanism:  Upregulates Ang-1 (BBB-stabilizing factor) and downregulates VEGF in astrocytes and pericytes; increases clearance of peritumoral edema by facilitating transport of fluid into ventricular system
Dosage:
  • Severe symptoms: 10mg IV loading dose then 4mg QID or 8 mg BID
  • Lower doses (1-2mg QID) may be as effective and less toxic
  • Long half life allows BID dosing
  • Improves within hours, maximum benefit within 24-72 hours, neuroimaging may not confirm until at least 1 week
  • If 16mg/day insufficient, may increase up to 100mg/day
  • Taper:  once improved, taper by 50% every 4 days
Guidelines:
  • severe symptoms:  16mg/d or more
  • milder symptoms: start 4-8mg daily
  • asymptomatic: steroids not recommended
  • taper over 2 week period or longer
Complications:
  • Insomnia, essential tremor, hiccups
  • GI complications
  • Steroid myopathy – prox weakness in week 9-12
  • PCP infection – risk increases while tapering steroids; fever and dyspnea and dry cough but can be subtle and nonspecific
Novel treatments:
  1. bevacizumab (anti-VEGF monoclonal antibodies)
  2. corticotrophin-releasing factor
  3. COX-2 inhibitors?

 

 

 

Anti-factor Xa Levels (Enoxaparin and Heparin)

*Standard dosing (enoxaparin 30 q12h) may be inadequate in high risk trauma; lead to inc rates of DVT

Monitor antifactor Xa level

  • Normal value = <0.1
  • >0.5 considered therapeutically anticoagulated
  • 0.2 to 0.5 considered target level for prophylaxis

–Send trough before 4th dose

  • If normal –>increase to 40mg q12h; then 50 sq q12h or even 60 q12h

–With this approach, majority of patients require enoxaparin in 40 q12h dose

(Marino)

 

Patients with morbid obesity or renal failure may require monitoring of Anti-Xa levels.

  • anti-Xa levels in plasma should be measured 4 hours after LMWH administration
  • desired anti-Xa level = 0.6-1.0 units/mL for BID dosing and >1 unit/mL for OD dosing

 

Early RCTs on LMWS excluded the following patients:

1. BMI>50 kg//m2

2. Pregnant

3. Renally impaired (Cr clearance <30 ml/min)

 

UFH affects Factor II and Factor Xa, LMWH affects predominantly Factor Xa.

Peak anti-factor Xa level is reached 3-5 hours after administration.

 

Suggested peak anti-factor Xa levels for enoxaparin (therapeutic):

1. BID dosing – 0.6 to 1.0 IU/mL

2. OD dosing – 1.0-2.0 IU/mL

 

Table. Target anti-factor Xa ranges for therapeutic anticoagulation with LMWH.

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Target range for prophylactic doses of LMWH not well defined.

Table. Target anti-factor Xa ranges for prophylactic doses of LMWH.

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Limited evidence available, but guidelines by ACCP suggests use of increased doses of LMWH perioperative for bariatric patients. Anti-factor Xa monitoring is recommended in patients with high-risk trauma and burns. Critically ill patients on inotropes may also be subtherapeutic on LMWH due to impaired peripheral circulation.

 

Table.  Target anti-factor Xa ranges for thromboprophylaxis in bariatric patients.

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BOTTOM LINE:  Reasonable anti-factor Xa target range is 0.2-0.5 IU/mL. Prospective studies are required to validate this recommendation.

ab

Therapeutic_Unfractionated_Heparin_Infusion_Guideline.pdf

References

Marino, P. and Sutin, K. (2007). The ICU book. Philadelphia: Lippincott Williams & Wilkins.

Wei, M. and Ward, S. (2015). The anti-factor Xa range for low molecular weight heparin thromboprophylaxis. Hematology Reports, 7(4).

https://www.uwhealth.org/files/uwhealth/docs/anticoagulation/Therapeutic_Unfractionated_Heparin_Infusion_Guideline.pdf