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Red alert: Avoid brimonidine and oxymetazoline as hemostatic agents

DII small banner By Warren R. Heymann, MD
June 19, 2017

Mohs micrographic surgery procedure including brimonidine treatment: skin before application (A), 5 minutes after application of brimonidine (B), and minimal intraoperative bleeding with pretreatment of brimonidine (C).
Credit: JAAD
As a youth, I recall that “rosy cheeks” were a sign of good health and would watch amusingly as my late aunt Hilda would excuse herself to put on her rouge. No more. In 2017, it’s time to get the red out, whether masked by green-tinted makeup, treated by intense pulsed light or pulsed dye laser, or by vasoconstrictors such as brimonidine (Mirvaso  0.33% gel) or oxymetazoline (Afrin 0.05% spray, Rhofade 1% cream).

One of the joys of practicing dermatology is being therapeutically creative for off-label use of topical agents. Both topical brimonidine and oxymetazoline have been used by ENT physicians and ophthalmologists for hemostasis, so it is only natural that dermatologic surgeons would adapt this technique to limit hemorrhage during procedures.

Shagalov et al presented two cases, a 70+ year-old man having Mohs micrographic surgery for a squamous cell carcinoma and a 90+ year-old man undergoing electrodessication and curettage of a large actinic keratosis adjacent to a seborrheic keratosis. Patients were treated with 10 g of brimonidine 0.33%, gel applied under occlusion for hemostasis. Both patients experienced deterioration of mental status, respiratory depression, and somnolence. Results from cardiac testing, laboratory workup, and imaging were negative for cardiac or neurologic etiology. Both patients improved in less than 24 hours (1).

Combigan is an ophthalmic solution that combines 0.2% brimonidine, a selective alpha-2 adrenergic agonist, with 0.5% timolol, a nonselective beta-adrenergic antagonist, approved for glaucoma. According to Gill et al, there have been recent reports of successful treatment of superficial infantile hemangiomas using topical Combigan. They reported the case of a 2-month-old girl who developed life-threatening brimonidine toxicity requiring intubation and mechanical ventilation secondary to central nervous system depression and apnea after topical application to an ulcerated IH (2).
As Shagalov et al suggest, the brimonidine toxicity in their patients resulted from being applied to open wounds. Being lipophilic, the drug easily crosses the blood-brain barrier, leading to CNS depression, manifesting as altered mental status, respiratory failure, and somnolence (1). Interestingly, the functional status of platelet alpha 2-adrenoceptors in patients with major depression has been assessed by simultaneously measuring both a biochemical mechanism of transduction of receptor activation (inhibition of adenylate cyclase activity) and a physiologic response of the receptor (induction of aggregation). In depressed (n = 30) and euthymic (n = 11) patients as well as in control subjects (n = 66), there was a clear dissociation between inhibition of adenylate cyclase activity and induction of aggregation, indicating that the two responses represent different phenomena of alpha 2-adrenoceptor activation (3). The precise pathogenesis of mental status changes due to brimonidine awaits elucidation.

Oxymetazoline, a selective alpha-1 agonist, partial alpha-2 agonist, and potent vasoconstrictor, has been utilized topically to reduce intraoperative persistent slow bleeding during between layers of Mohs surgery. This has been useful in patients who report intolerance to anesthetics containing epinephrine or taking anticoagulants. Phillips and Huang have not encountered any untoward effects, although they acknowledge that further study for the use of oxymetazoline for hemostasis is warranted (4). Toxicity from oxymetazoline, however, has been reported. Fabi et al detail the case of a 23 month-old boy who developed hypotension, bradycardia, and lethargy a few minutes after using inhaled 0.05% oxymetazoline,  prescribed for rhinorrhea.  He improved within several hours. The authors note that hypertension, tachycardia, and generalized peripheral vasoconstriction are the usual signs of systemic toxicity, but in some patients stimulation of the centrally located alpha-2 receptor may produce a strong hypotensive-bradycardic reaction. (5)

According to Epocrates, while no serious reactions have been reported with Rhofade, bradycardia and hypotension are listed for Mirvaso. In my experience flushing and rebound occur with Mirvaso, so I only prescribe it rarely. Every Rhofade prescription I have written has been denied, so I really do not have much experience with it yet. I have used Afrin with reasonable success and essentially no adverse reactions, since Shanler et al reported its efficacy in their brilliant Cutting Edge article a decade ago (Arch Dermatol 2007; 143: 1369-71).

I am not very concerned about systemic absorption of these products on intact  skin, and do not anticipate reading about toxicity when prescribed as directed for erythematotelangiectatic rosacea. My surgical practice is about as minor as you can get — I stopped using Monsel solution years ago because of the tattoo effect; I usually get hemostasis with aluminum chloride and electrocautery. Based on the current literature, I wholeheartedly concur with Shagalov et al who “urge against the use of topical brimonidine as a hemostatic agent until its use is further investigated.” (1) I would say the same for oxymetazoline.

1. Shagalov DR, et al. Association of central nervous system depression with topical brimonidine when used for hemostasis: A serious adverse event. JAMA Dermatol 2017: 153: 575-7.
2. Gill K, et al. Brimonidine toxicity secondary to topical use for an ulcerated hemagioma. Pediatr Dermatol 2016; 33: e232-4.
3. García-Sevilla JA, et al. Alpha 2-adrenoreceptor-mediated inhibition of platelet adenylate cyclase and induction of aggregation in major depression. Effect of long-term cyclic antidepressant drug treatment. Arch Gen Psychiatry 1990; 47: 125-32.
4. Phillips CB, Huang CC. Topical oxymetazoline hydrochloride 0.05% as a strategy to reduce intraoperative wound oozing in Mohs micrographic surgery. Dermatol Surg 2015; 41: 749-50.
5. Fabi M, et al. Are nasal decongestants safer than rhinitis? A case of oxymetazoline-induced syncope. Cardiol Young 2009; 19: 633-4.

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