Summary: Medications and Allergies

undergoing dermatologic surgery for benign and malignant lesions [20]. This study found a sixfold increased risk of moderate to severe bleeding complications in patients taking warfarin compared to controls (12.3% versus 2.1%, respectively). Patients taking aspirin had a nonsignificantly increased risk of bleeding with a 4.0% rate of moderate to severe complications. Clopidogrel is a newer anticoagulant with extensive use in cardiology after intracoronary stent placement for myocardial infarction, and has synergistic antiplatelet effects when combined with aspirin. The effect of clopidogrel on bleeding complications in dermatologic surgery has not been well studied, but our own experience and published data from the general medical literature suggest that the combination of aspirin and clopidogrel is similar to warfarin in terms of bleeding risk [21]. The surgeon can therefore expect an increased incidence of postoperative bleeding in patients treated with anticoagulant medications and should take the necessary precautions to ensure adequate hemostasis in these patients. These include rigorous control of any bleeding or oozing with ligation or cautery intraoperatively and the use of pressure dressings for at least 24 h postoperatively.

Given the small but demonstrable increased risk of postoperative bleeding in patients treated with anticoagulants, it is reasonable to question whether stopping anticoagulant therapy prior to the planned procedure would mitigate this risk. Although stopping these medications was an accepted practice among dermatologic and plastic surgeons 10–20 years ago, several pharmacologic and physiologic aspects of these medications must be recognized when considering a temporary cessation of anticoagulation. First, aspirin and clopidogrel cause an irreversible inhibition of platelet function that can only be recovered by the synthesis of new platelets; the lifespan of circulating platelets is 7–10 days. Warfarin inhibits synthesis of serum coagulation proteins such as factor II, VII, IX, and X; the half-life of these factors in serum ranges from 1 to 3 days. Thus, recovery of platelet and clotting factor function requires at least 4–7 days of therapy cessation prior to any scheduled procedure. Second, resumption of the therapeutic antithrombotic effect requires another 4–7 days after the anticoagulant is initiated due to the gradual decay of serum clotting factors or inhibition of platelet function. Third, compensatory factors induced by chronic anticoagulant treatment, such as decreased levels of protein C and S or increased

activity of other clotting factors, may lead to a transient hypercoagulable state when these medications are interrupted. It is therefore likely that interruption of anticoagulant therapy for a 1–2-h superficial procedure could result in up to 2 weeks of significantly increased risk of systemic thrombosis.

Several case reports in the literature have described catastrophic thrombotic events when therapeutic anticoagulation was held for cutaneous surgery. Schanbacher and Bennett reported two patients who suffered acute thrombotic stroke when warfarin was held for Mohs surgery of facial basal cell carcinoma [22]. In both cases, warfarin was held for 1 week prior to surgery, restarted the day following the procedure, and the thrombotic complications occurred 3–4 days after the procedure. Of note, anticoagulation in both cases was interrupted under consultation with the patient’s internist or cardiologist. Holding therapy with antiplatelet agents can also have deleterious effects, as reported in one case of major pulmonary embolus and one case of prosthetic aortic valve thrombosis when dual anticoagulant therapy (aspirin and ticlopidine in one case and clopidogrel and ardeparin, a low-molecular weight heparin in the other, respectively) was stopped 7 days prior to surgery [23]. In both cases, the thrombotic event occurred 2–3 days after surgery. To estimate the incidence of these rare adverse events, Kovich and Otley performed a survey of Mohs surgeons to discover 46 cases of adverse thrombotic events attributed to cessation of anticoagulation therapy. These included 24 strokes, 3 cerebral emboli, 5 myocardial infarctions, and 3 deaths [24]. Based on the average rate of warfarin and aspirin use in dermatologic surgery patients and the extrapolated number of cases performed by each surgeon, the authors estimated an incidence rate of 1 in 6,219 operations for warfarin cessation and 1 in 21,448 for aspirin cessation. A more systematic review of published cases from the dental literature found 542 cases in which warfarin therapy was suspended, and 5 cases of thrombotic complications, 4 of which were fatal [25]. This nearly 1% incidence of complications is almost certainly an overestimate, however, as the previously common practice of warfarin cessation prior to oral surgery was not routinely reported in the literature.

Using data from these studies, one can determine the relative risk-to-benefit ratio of holding or continuing therapeutic anticoagulation prior to cutaneous surgery. For warfarin therapy, there does appear to be a

modest increase in local bleeding complications when warfarin is continued perioperatively. As noted above, however, no cases of death or hemodynamically significant hemorrhage have been reported in cutaneous surgery from continuation of anticoagulant use. In contrast, nearly all the reported cases of thromboembolic complications associated with cessation of warfarin therapy, though rare, have resulted in death or permanent disability. The recommendation, therefore, is that warfarin treatment should not be suspended for any length of time for dermatologic surgery. Aspirin appears to have a lower risk of hemorrhagic complications when continued throughout cutaneous surgery, and it should likewise be continued in patients taking aspirin for coronary artery disease or other thrombotic tendency. While the risk-to-benefit ratio of clopidogrel has not been defined in these studies, the American College of Cardiology recommends that patients taking clopidogrel after myocardial infarction should remain on their anticoagulant therapy during minor surgical procedures such as local skin surgery [6]. One situation where anticoagulant medications should be interrupted in dermatologic surgery is when a patient is taking aspirin or other NSAIDs for pain relief, rather than for the anticoagulant effect. In this case, we advise the patient to suspend NSAIDs for 1 week before and 2 days after the surgical procedure. Pain relief in the perioperative period can then be managed with acetaminophen.

In addition to therapeutic anticoagulants, several herbal or over-the-counter (OTC) medications can have intended or unintended effects on the coagulation pathway. It is important for the surgeon to be cognizant of these medications. Because patients may not be aware of the anticoagulant effects, the surgeon must specifically question patients about use of these traditional and nontraditional medications. Several common OTC medications contain aspirin or ibuprofen as the active ingredients, such as Alka-Seltzer and Advil Cold and Sinus, respectively. Herbal medications and supplements have also been implicated in several cases of spontaneous or postoperative bleeding, including one report of serious hemorrhage requiring transfusion after uncomplicated laparoscopic cholecystectomy in an otherwise healthy 36-year-old man taking Ginkgo biloba supplements [26]. These reports of hemorrhagic complications are supported by mechanistic studies showing that Ginkgo extracts reduce blood viscosity and inhibit platelet

activating factor. Isolated case reports and in vitro studies of platelet activation and coagulation factors have also implicated garlic, ginseng, ginger, feverfew, vitamin E, and saw palmetto in exacerbated operative and postoperative bleeding [27, 28]. For all these agents, however, definitive studies of bleeding risk have not been performed, and it remains difficult to assess whether the published case reports represent causality or coincidence. Nevertheless, because these supplements are used primarily for prevention rather than treatment and because there is no known risk of stopping these products, it is recommended that patients discontinue the use of Ginkgo biloba, garlic, ginseng, ginger, feverfew, vitamin E, and saw palmetto 1 week prior to surgery. Another herbal product that should also be stopped is ephedra, or ma huang, a Chinese herbal remedy with sympathomimetic properties that has been reported to cause insomnia, hypertension, arrhythmia, and stroke; these effects may be magnified when combined with epinephrine used in cutaneous surgery [27].

The use of nonselective beta-blockers such as propranolol has prompted concern for interactions with subcutaneous epinephrine since the initial report of six cases of profound intraoperative hypertension, including one case of nonfatal cardiac arrest [29]. A subsequent prospective study of ten patients on propranolol undergoing Mohs surgery, however, found no change in blood pressure after administration of typical doses of subcutaneous epinephrine [30]. All six cases of epinephrine-induced hypertension in the original report were undergoing facial and eyelid plasty, and were treated with initially large volumes of subcutaneous lidocaine with epinephrine (8–40 cc at 1:100,000 or 1:200,000 dilution); this quantity of epinephrine is not typically used in Mohs surgery in a single injection. Moreover, the majority of beta-blockers in use today (such as metoprolol and atenolol) are selective for the myocardial beta 1 receptor without pharmacologic binding to beta 2 receptors on the peripheral vasculature. Thus, these selective beta-blockers are not expected to lead to unopposed alpha receptor activity in the presence of epinephrine to the same extent as propranolol (a nonselective beta 1 and 2 blocker). In light of the clear cardioprotective effects of beta-block- ers and other antihypertensive medications, particularly in the perioperative period, these medications should be continued at their usual dose in patients undergoing dermatologic surgery.

Several other medications commonly used by patients may also be relevant to dermatologic surgery and should be noted in the preoperative evaluation. Patients with diabetes mellitus should be counseled to take all of their usual medications on the day of surgery, including insulin. At the same time, they must be instructed to follow their normal eating habits on the day of surgery to prevent hypoglycemia. Similarly, diabetic patients must be monitored for symptoms of hypoglycemia during prolonged Mohs cases and provided with food or carbohydrate-rich beverages as appropriate. The increasing use of biologic agents for tumor necrosis factor alpha (TNFa) inhibition in patients with psoriasis, rheumatoid arthritis, and inflammatory bowel disease necessitates a working knowledge of the interactions of these medications with wound healing after surgery. TNFa is a cytokine with a central role in both the inflammatory phase of appropriate wound healing and in innate immune activation to limit infection. One retrospective study of rheumatoid arthritis patients found that continuing treatment with TNFa antagonists during elective orthopedic surgery resulted in a fourfold increased risk of postoperative infection compared to matched controls. Other diseasemodifying antirheumatic agents such as methotrexate did not demonstrate this increased risk [31]. Although it is unclear whether similar complications can be expected from TNFa antagonists in dermatologic surgery, it may be prudent to hold these medications for 1–2 weeks perioperatively when performing larger procedures or more complex repairs. Finally, patients under the care of a dermatologist are likely to be using topical medications such as retinoids, corticosteroids, chemotherapeutics such as 5-fluorouracil, and immune modulators such as imiquimod. To prevent interference with appropriate wound healing, patients should be advised not to apply these medications to the area around the surgical site for at least 1 week before and 2 weeks after surgery, unless they are prescribed as specific adjunctive therapy for the malignancy to be treated.

Apart from documenting the patient’s current medications at the preoperative evaluation, any suspected allergies to medications or skin contactants must be clearly recorded in the patient’s medical record. Relevant allergies in dermatologic surgery are most often limited to antibiotics, anesthetics, preservatives in anesthetics, and adhesives in tape and dressings. Antibiotic allergies are the most common, and

equivalent antibiotics from a different class are often easily substituted. Allergies to local anesthetics are unusual. When present, they often present as local contact allergies to anesthetics of the ester class such as procaine. Amide anesthetics such as lidocaine are almost universally tolerated, but there have been systemic allergic reactions reported in the literature. In one case, systemic urticaria without anaphylaxis occurred within minutes after amide anesthetic administration, and subsequent challenge confirmed amide anesthetic reactivity without any reaction to ester anesthetics or preservatives [32]. Allergies to preservatives such as methylparaben or sodium metabisulfite contained in multidose vials have also been described. When a patient reports a previous reaction to a local anesthetic, it is imperative to determine the nature of the reaction, whether the reaction was local or systemic and what anesthetic and additives were used when the reaction occurred. This can allow determination of whether there is true allergy, and whether the allergy is likely to be to anesthetics of the ester class, amide class, or preservatives. When in doubt, patients may be challenged with preservative-free (sold in single-dose ampoules) anesthetics of either class, or may be referred to an allergist for skin prick testing. This testing may be cumbersome and delay surgery, but it is clearly indicated to spare the patient from potentially unnecessary exposure to general anesthesia for the remainder of their lifetime. Although “allergic reactions” to epinephrine may be self-reported by patients, true allergy to epinephrine is physiologically implausible as this is an endogenous hormone and neurotransmitter. More often, these self-reported reactions are the expected physiologic side effect of small amounts of epinephrine reaching the systemic circulation: transient flushing, anxiety, tachycardia, or palpitations. These reactions are not a contraindication to subsequent use of subcutaneous epinephrine in cutaneous surgery. Reactions to adhesives in medical tape and wound dressings are common and should also be noted at the preoperative evaluation. Because these local reactions are often partly due to irritant dermatitis, substitution with a weaker adhesive (such as use of paper tape instead of silk or synthetic tape) is often helpful in reducing local skin irritation. Asking patients which types or brands of adhesive dressings they have tolerated in the past will also help to minimize postoperative dermatitis and patient complaints.