Use of dexamethasone for vasogenic edema

Vasogenic edema is a result of a disruption of the blood brain barrier that is frequently related to tumors.  The edema can lead to increased intracranial pressure in addition to tissue shifts and brain displacement.  Injury can occur not only from this mechanical shift but also from decreased perfusion that is associated with elevated intracranial pressure.

Dexamethasone is a potent, long-acting glucocorticoid which has no inherent mineralocorticoid activity.  Glucocorticoids have a number of mechanisms for how they reduce inflammation in the body including reduction in lymphocytes, monocytes, basophils, and eosinophils (neutrophils decrease at the site of inflammation but increase in the blood); suppression of the arachadonic acid cascade by inhibiting phospholipase A2 which reduces prostaglandins and leukotrienes; inhibition of other antigen presenting cells; vasoconstriction and decreased capillary permeability; and at large doses, reduced production of antibodies.

The mechanism by which glucocorticoids reduce vasogenic edema is not completely understood.  It is proposed to be due to inhibiting the vascular endothelial growth factor (VEGF) (which is one of the causes of increased vascular permeability) and by increasing Ang-1 (a blood brain barrier stabilizing factor).  Reduction of symptoms may begin within a few hours after starting dexamethasone but improvement on an MRI may not occur for 48 hours to a week.  

As dexamethasone and other steroids are associated with a litany of dose-related side effects, it is prudent to administer the lowest effective dose possible. 

So what dose and frequency to use?

A wide range of doses of dexamethasone have been used for vasogenic edema.  The FDA-approved labeling indicates an initial dose of 10 mg IV followed by 4 mg every six hours IM.  For maintenance therapy, they recommend that 2 mg twice or three times daily may be effective. 

A review was published in 2010¹ that was only able to identify two high quality studies addressing the questions if steroids improve neurologic symptoms and if so, what dose should be used.  The first study examined patients that were not felt to be at risk of impending herniation and compared 4, 8, and 16 mg per day.  No difference was found in Karnofsky performance scores (administered periodically over four weeks) but patients receiving the higher doses did have more adverse effects (ie. Cushingoid changes and extremity edema).  The next study gave an initial dose of 24 mg every six hours IV to everyone and then randomized patients to either 4 mg every six hours or nothing.  No statistical analyses were done because the same sizes were too small and they could not make any recommendations.  One observation that I think is noteworthy is that only 33% of patients responded to the initial large dose that everyone was given (24 mg q6 hour).

There have been other studies examining these questions but I will summarize the findings in the following medication pearls:

• Use corticosteroids only for symptomatic relief of CNS symptoms of brain metastases – if there are no symptoms, or impending herniation, don’t use steroids
• Dexamethasone is the preferred choice because of a lack of mineralocorticoid activity
• Dexamethasone’s long biologic half-life (36-54 hours) make twice daily dosing sufficient – although more frequent dosing has been suggested if there’s concern for impending herniation
• Starting doses of 4-8 mg per day are recommended for most patients, unless there are severe symptoms where 16 mg per day should be considered
• There is a paucity of information in the literature to guide these recommendations and to even indicate that steroids are effective at all.  Alternatively, there is also little information indicating that they are not effective.

• Tablets sizes available:  0.5, 0.75, 1, 1.5, 2, 4, 6 mg

References:

1.  Ryken TC, McDermott M, Robinson PD, et al.  The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline.  J Neurooncol  2010;96:103-114.

2.  Dexamethasone.  Micromedex.  Available at:  www.micromedexsolutions.com

3.  Dexamethasone prescribing information.  Roxane Laboratories.  September 2007.

4.  Chrousos GP. Chapter 39. Adrenocorticosteroids & Adrenocortical Antagonists. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12nd ed. New York: McGraw-Hill; 2012. http://www.accesspharmacy.com/content.aspx?aID=55828042.