ORIGINAL ARTICLE. Surgical Resection of Cutaneous Head and Neck Lesions. Muthuswamy Dhiwakar, MS, MRCS; Najib A. Khan, FRCS; Leo G.

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1 ORIGINAL ARTICLE Surgical Resection of Cutaneous Head and Neck Lesions Does Aspirin Use Increase Hemorrhagic Risk? Muthuswamy Dhiwakar, MS, MRCS; Najib A. Khan, FRCS; Leo G. McClymont, FRCS Objective: To determine whether the antiplatelet agent aspirin increases hemorrhagic risk in patients undergoing surgical resection of cutaneous head and neck lesions. Design: Retrospective cohort study. Setting: Regional referral center. Patients: All cases of cutaneous head and neck lesions surgically resected during a 10-year period were included. Main Outcome Measures: Outcome measures were incidence of significant postoperative hemorrhage, defined as postoperative hematoma or hemorrhage necessitating surgical reexploration; and total postoperative hemorrhage, defined as any hemorrhage lasting longer than 4 hours despite external pressure, requiring medical review, and resulting in prolongation of the patient s hospital stay or readmission to the hospital. Results: Seven hundred eleven patients (974 cases) were eligible for inclusion, of whom 320 were receiving aspirin therapy at the time of surgery. The incidence of significant postoperative hemorrhage in the aspirin and nonaspirin groups was 5 (1.6%) and 0, respectively (P=.004), and aspirin use was the only risk factor for significant postoperative hemorrhage. The incidence of total postoperative hemorrhage in the aspirin and nonaspirin groups was 7 (2.2%) and 1 (0.1%), respectively (P=.002). At multivariate analysis, aspirin use and local flap reconstruction were independent risk factors for total postoperative hemorrhage. Cases receiving aspirin therapy who also underwent local flap reconstruction were at exponential (124-fold) increased risk of total postoperative hemorrhage compared with cases with neither risk factor. Conclusions: Aspirin intake at the time of surgery to resect cutaneous head and neck lesions confers a small but statistically increased risk of postoperative hemorrhage. This risk is particularly pronounced in patients undergoing local flap reconstruction. Arch Otolaryngol Head Neck Surg. 2006;132: Author Affiliations: Department of Otolaryngology Head and Neck Surgery, Raigmore Hospital, Inverness, Scotland. SKIN CANCER IS THE MOST COMmon cancer worldwide. Surgical excision remains the treatment of choice and offers cure rates and cosmetic outcomes comparable with, if not superior to, alternate methods of treatment. 1 However, these lesions typically occur in elderly patients, many of whom are taking the antiplatelet agent aspirin because of its cardiovascular protective effects. Population-based data from the United States reveal that at least 25% of middleaged and elderly adults take regular aspirin. 2 However, the risk of hemorrhagic complications with aspirin use during excision of cutaneous lesions is unclear and has not been well quantified. This has led to considerable variation and lack of consensus among surgeons about continuing vs discontinuing aspirin therapy before surgery. 3 Rapid advances in health care are enabling more people to progress into old age while maintaining relatively healthy and active lifestyles. At the same time, the future incidence of skin cancers is projected to rise steeply, with most lesions involving the head and neck region. 4 Patients taking antiplatelet agents such as aspirin who have head and neck skin lesions are likely to compose an increasing proportion of the workload for facial plastic and oncologic surgeons. Knowledge of the risks associated with aspirin therapy, hitherto lacking, will, therefore, be crucial in determining the most appropriate perioperative management. We examined whether 1237

2 aspirin therapy or any covariable increased the risk of postoperative hemorrhage or impaired wound healing after surgery to resect cutaneous lesions of the head and neck. METHODS A 10-year retrospective case review of all surgical resections of cutaneous lesions of the head and neck performed at the Department of Otolaryngology Head and Neck Surgery, Raigmore Hospital, Inverness, Scotland, from January 1, 1996, to December 31, 2005, was undertaken. The unit serves as the regional referral center for head and neck plastic surgery for the Highlands of Scotland. Cases were identified from a universal electronic database using procedure-specific codes. A predefined data extraction sheet was used. The primary data source was the patient medical record in which physician and nurse entered all patient demographic data, current medications, and management details in separate, unique, and structured forms in parallel fashion. The nurses form also included specific provisions for recording the time of occurrence of postoperative events and the dryness and appearance of the wound. In addition, a comprehensive review of consolidated discharge summaries, drug prescription and consumption charts, outpatient records, electronic databases of operative details, and primary care records was undertaken to correlate, confirm, and collect any missing data. The policy in our department is to not stop aspirin therapy preoperatively. Patients were considered to have taken aspirin if the drug had been consumed within 4 days before surgery. Patients not taking regular aspirin and who had not consumed the drug within 5 days before surgery were considered control subjects for comparison. This time frame was chosen because aspirin irreversibly inhibits platelet function for the life of the platelet (ie, approximately 7-10 days). Therefore, after 5 days, half of all circulating platelets would be newly produced and functional and would be ample for adequate hemostasis. 5 Patients were considered to have taken a nonsteroidal anti-inflammatory drug if it had been consumed within 3 days before surgery. 5 For this study, the consultant was considered the surgeon if he or she performed or assisted in the procedure, and the trainee was considered the surgeon if he or she performed the procedure independent of the consultant. Blood and coagulation data were not routinely checked preoperatively. For surgery, local anesthesia was preferred, with a standard preincisional infiltration of 2% lignocaine and 1: epinephrine tartrate. A surgical knife was used for incision and dissection. Bipolar diathermy was used for hemostasis, and, when possible, the wound was closed in layers. The method of repair was determined by the site and size of the defect and the choice of the individual surgeon. When primary closure was impossible, a variety of local flaps (simple rotation, bilobed, rhomboid, nasolabial, forehead, melolabial, advancement [single, bilateral, and V-Y], fan, Karapandzic, and Abbe-Estlander) or skin grafts were used for skin cover. Dressings were not applied. Acetaminophen (0.5-1 g 4 times daily) with or without codeine (30-60 mg 4 times daily) was prescribed for analgesia, and patients were observed for 2 to 4 hours in the recovery unit before discharge. Sutures were removed on postoperative days 5 to 7. Follow-up was at the clinic at 1 to 4 weeks postoperatively or until the wound had satisfactorily healed. OUTCOME MEASURES Primary Outcome Measures Significant postoperative hemorrhage (SPH) was defined as postoperative hematoma or hemorrhage necessitating surgical reexploration; total postoperative hemorrhage (TPH) was defined as any hemorrhage lasting longer than 4 hours despite external pressure, requiring medical review, and resulting in prolongation of the patient s hospital stay or readmission to the hospital. Hematoma was defined as the development of a tender, tense, and discolored swelling that raised the wound or flap and from which clotted or collected blood was expressed or aspirated. Secondary Outcome Measure Wound healing, assessed at 1 to 4 weeks postoperatively, was determined by the incidence of partial or complete necrosis of flap or graft, or wound dehiscence greater than 5 mm as a result of hematoma, seroma, infection, or indeterminate cause. Minor complications such as crusting, ecchymosis, and serous oozing were not considered. Excluded from the study were patients undergoing incisional biopsy, Mohs micrographic surgery, excision of noncutaneous cystic and soft tissue lesions, excision and healing by secondary intention, concomitant neck dissection, or adjacent salivary gland or bony resection, those with primary bleeding disorders, and patients receiving warfarin sodium therapy. STATISTICAL ANALYSIS Univariate analysis was performed to identify possible risk factors for SPH and TPH. Variables analyzed were age and sex; medical illness, overall and individually for hypertension, peripheral vascular disease, renal failure, liver disease, and immunosuppression; previous radiotherapy to the head and neck region; intake of aspirin, nonsteroidal anti-inflammatory drug, or other antiplatelet agent, and prophylactic antibiotic agent; site of lesion, including scalp, nose, eyelid, ear, cheek, or neck; method of repair, such as simple closure or local flap or skin graft; dimension of resected skin; type of anesthesia (local or general); use of suction drain; histologic finding, including benign, preinvasive, or malignant lesion; and grade of surgeon (consultant or trainee). For univariate analysis, we used the Mann-Whitney test for continuous variables and the 2 or Fisher exact tests, as appropriate, for categorical variables. Risk factors associated with any category of hemorrhage with a P.05 at univariate analysis were included in the multivariate logistic regression model to adjust for possible confounding factors. Epi-Info (version 3.3; Centers for Disease Control and Prevention, Atlanta, Ga) was used for statistical analysis. RESULTS We identified 1006 cases from the electronic database. The medical records for 14 of these patients were unavailable. In another 18 patients, none of whom experienced postoperative hemorrhage, details of medication intake at the time of surgery were unclear. Thus, 974 cases (711 patients) were eligible for inclusion. Table 1 lists the characteristics of the included cases. In patients given aspirin, the dose varied from 75 to 300 mg. Suction drains were not routinely used, but were used in 8 cases (0.8%), most of whom underwent resection of large scalp lesions with local flap reconstruction. Five cases experienced significant postoperative hemorrhage, all of whom were taking aspirin (P=.004). There was no other risk factor for SPH at univariate analysis; thus, multivariate analysis was not performed. Total postoperative hemorrhage occurred in 8 cases, 7 of whom were 1238

3 Table 1. Characteristics of Cases* Cases Characteristic (N = 974) Age, mean (±SD), y 69.9 (14.9) Sex, male/female 652/322 Medical illness 399 (42.3) Hypertension 354 (36.3) Renal failure 6 (0.6) Liver disease 2 (0.2) Peripheral vascular disease 10 (1.0) Immunosuppression 39 (4.0) Previous radiotherapy to head and neck 5 (0.5) Medication at time of surgery Aspirin 320 (32.8) Nonsteroidal anti-inflammatory drug 94 (9.6) Newer generation antiplatelet drug 19 (1.9) Peripheral vasodilator 4 (0.4) Prophylactic antibiotic 16 (1.6) Resected skin diameter, mean (±SD), cm (2.5) Site of lesion Scalp 173 (17.8) Nose 240 (24.7) Eyelid 17 (1.7) Ear 270 (27.8) Cheek 233 (23.9) Neck 40 (4.0) Anesthesia, local/general 826/148 Suction drain 8 (0.8) Method of repair Simple closure 604 (62.0) Local flap# 282 (29.0) Skin graft** 88 (9.0) Histologic findings Benign and preinvasive lesions 373 (38.3) Malignant lesions 601 (61.7) Surgeon, consultant/trainee 720/254 *Data are given as number (percentage) unless otherwise indicated. Dipyridamole, ticlopidine, or clopidogrel. Naftidrofuryl (Praxilene; Merck &Co, Inc, NJ). Including medial canthus. Including preauricular and postauricular regions. Including cutaneous surface of lips. #Including 25 cases in whom more than 1 local flap was used. **Including 86 full-thickness skin grafts, 1 partial-thickness skin graft, and 1 composite graft (ear cartilage and overlying skin). taking aspirin (P=.002). Local flap or skin graft repair and age were other possible risk factors for TPH (Table 2). At multivariate analysis, aspirin use and repair with local flap remained as independent risk factors for TPH (Table 2). In subgroup analysis of cases with primary closure, aspirin did not increase the risk of TPH (P=.13). In cases with local flap reconstruction, however, aspirin increased the risk of TPH (unadjusted odds ratio, 14.4; 95% confidence interval, ; P=.006). Similarly, cases taking aspirin who also underwent local flap reconstruction had a significantly increased risk of TPH compared with those with neither risk factor (adjusted odds ratio, 124; 95% confidence interval, ; P.001). All 7 cases with TPH had been taking aspirin throughout the period of observation. All cases with TPH underwent surgery while under local anesthesia; none had received previous radiotherapy; and none required blood transfusion postoperatively. Table 3 Table 2. Risk Factors for Total Postoperative Hemorrhage Risk Factor Univariate Analysis P Value Multivariate Analysis gives the characteristics of cases with TPH, and Table 4 gives details of management and complications in cases with TPH. Thirty-nine cases (4%) had impaired wound healing, and neither aspirin nor any other variable was a risk factor for this outcome. However, occurrence of both SPH and TPH was highly predictable of impaired wound healing (P.001 and.004, respectively; Table 4). Only 1 of 4 cases with hematomas, all with flap reconstruction, were returned to the operating room for surgical reexploration. The other 3 cases potentially merited surgical reexploration but instead were managed conservatively, and all 3 experienced necrosis of the flap (Table 4). Excluding cases with TPH, 5 cases with local flap repair experienced necrosis of the flap. One of these cases was taking aspirin (P=.67); hence, aspirin therapy did not protect against flap necrosis. COMMENT Adjusted Odds Ratio (95% Confidence Interval) Age ( ) Aspirin ( ) Local flap or skin graft ( ) Local flap, excluding skin grafts ( ) Findings from the present study show that surgical resection of head and neck cutaneous lesions in patients receiving aspirin therapy confers a higher risk of hemorrhagic complications. This is consistent with a recent meta-analysis that found that aspirin therapy increased postoperative hemorrhagic risk in several surgical procedures, in particular, intracranial surgery, prostatectomy, gastrointestinal endoscopy, tonsillectomy, and dental extraction. 3 Aspirin-related postoperative hemorrhage occasionally led to adverse surgical outcomes, including death. 3 However, the few studies that have analyzed cutaneous surgery failed to demonstrate such increased risk. 5-8 There are several possible reasons for this. In most studies, the number of patients recruited was small, limiting the power to detect differences in hemorrhage rates. 6-8 The largest study to date was performed by Otley et al, 5 who retrospectively studied 803 procedures but did not differentiate between hemorrhagic and nonhemorrhagic complications. This study was further nonspecific in that patients taking aspirin or nonsteroidal antiinflammatory drugs, 2 agents with distinct differences in pharmacodynamics and potency in platelet aggregation inhibition, were combined as a single study group. 5 Further, none of these studies focused exclusively on the head and neck region but included all regions of the body. 5-8 Head and neck plastic surgery differs from plastic surgery elsewhere owing to the greater emphasis on cosmesis and wider choice of local flaps and skin grafts. Because of proximity to cosmetically and functionally 1239

4 Table 3. Characteristics of Postoperative Hemorrhage Patient No./Sex/Age, y Yes/No Aspirin Dose, mg/d Medical Illness Concurrent Nonaspirin Antiplatelet Agent* Performed by Consultant Site Area of Resected Skin, cm 2 Method of Repair Histologic Finding Total Postoperative Hemorrhage 1/M/83 Yes 75 HT No Yes Ear 3.8 Simple closure SCC 2/F/70 Yes 75 HT No Yes Eyelid 3 Rhomboid flap BCC 3/M/81 No... No No Yes Nose 3.6 Bilobed flap BCC Significant Postoperative Hemorrhage 4/M/83 Yes 75 No No Yes Scalp 36.5 Rhomboid flap Spindle cell variant of SCC 5/F/84 Yes 75 HT No Yes Nose 5.8 Nasolabial flap BCC 6/M/74 Yes 75 No No Yes Scalp 10 Rhomboid flap Bowen disease 7/M/76 Yes 75 No No Yes Scalp 13 Rhomboid flap BCC 8/M/82 Yes 75 HT No No Ear 10 Simple closure SCC Abbreviations: BCC, basal cell carcinoma; HT, hypertension; SCC, squamous cell carcinoma. *Nonsteroidal anti-inflammatory drug, dipyridamole, ticlopidine, or clopidogrel. Suction drain inserted because of resection of large lesion with flap reconstruction. Table 4. Management of Postoperative Hemorrhage Postoperative Hemorrhage Patient and Management Total Postoperative Hemorrhage 1 Hemorrhage for 16 h, significant bruising; pressure bandage 2 Hemorrhage for 12 h, significant periorbital bruising 3 Hemorrhage for 16 h, significant periorbital bruising Significant Postoperative Hemorrhage 4 Hemorrhage for 48 h; suction drain removed 48 h postoperatively; at 1 wk, hematoma under flap, expressed after stitch removal; pressure dressing and 5 Acute hematoma 3 h postoperatively; return to operating room, wound reexplored, bipolar diathermy to bleeding point under flap; suction drain and antibiotic therapy 6 Hemorrhage for 24 h, hematoma twice (at 24 and 72 h); on both occasions, aspirated blood; pressure bandage and 7 Hemorrhage for 72 h; at 1 wk; hematoma under flap, expressed after stitch removal; pressure dressing and 8 Hemorrhage for 6 h; returned to operating room for reexploration; stitching at bleeding point Complications of Wound Healing Necrosis of tip of flap Flap necrosis Flap necrosis sensitive structures, facial wounds, unlike wounds elsewhere, are not routinely amenable for postoperative pressure dressings or insertion of drains. Anatomically, the head and neck region is distinguished by its rich vascular supply and the intricate relationship between its superficial fascia, areolar and dense fibrous tissue planes, and deep fascia. 9 Thus, results derived from general cutaneous series cannot be reliably applied to the head and neck region. Only 1.6% to 2.2% of cases taking aspirin in the current study experienced postoperative hemorrhage. This rate is lowerthanthatcitedfornoncutaneoussurgery. 3 Whilevariations in the definition of hemorrhage may be a factor, the lower rate is also attributable to the easier accessibility of cutaneous wounds, which facilitates external pressure tamponade in the recovery unit, thereby potentially mitigating the severity of hemorrhage, enhancing the likelihood of achievinghemostasisandpreventingacutehematomas, thus reducing the need for surgical reexploration. Aspirin causes irreversible loss of the cyclooxygenase activity of platelet prostaglandin (PG) G and PGH synthase 1. This results in decreased conversion of arachidonate to PGG 2 and, ultimately, of PGH 2 and thromboxane A 2, which are important mediators in platelet aggregation and thrombi formation. Platelets are exquisitely sensitive to aspirin. A dosage of only 30 mg effectively eliminates the synthesis of thromboxane A The minimum documented dosage of aspirin in our patients (75 mg) is higher than this threshold. Experimental animal models have demonstrated that aspirin therapy attenuates the vasospasm after hemorrhage. 11 Thus, we postulate that, even after apparently adequate hemostasis at the completion of surgery, the failure to form adequate and stable thrombi, in concert with an attenuated vasospastic response, predispose to postoperative hemorrhage from capillaries and small to medium vessels. The increased risk of TPH with local flap reconstruction is attributable to more extensive tissue mobilization and a potentially larger dead space created under the flap. Some shortcomings of this study must be noted. First, all retrospective studies include incomplete data and have limited scope for standardization. However, in this study, multiple sources were used to collect, correlate, and confirm the data, thereby minimizing deficiencies and maximizing accuracy. Only the most morbid, clinically rel- 1240

5 evant, and objectively evaluable factors have been used to define hemorrhagic outcomes. A prospective study is ideal but would not be cost-effective, given the infrequent occurrence of postoperative hemorrhage. Second, smoking was not examined as a risk factor, although it has been implicated as compromising cutaneous wound healing and survival of facial cutaneous flaps. 12 However, smoking exerts its deleterious effects through its thrombogenic, vasospastic, and deoxygenating potential 12,13 and is not known to enhance bleeding after cutaneous surgery. Third, because surgeons were not blinded to patient medication intake, more care could have been exercised in achieving hemostasis in the aspirin group, thereby biasing the results toward underestimating the hemorrhagic potential of aspirin therapy. The implications of the findings of the present study need to be examined in a larger clinical context. Overall, the risk of hemorrhage with aspirin therapy is small and the outcome is nonfatal. However, the safety of temporary discontinuation of aspirin therapy is unclear; some anecdotal evidence suggests that it may predispose to a small risk of thromboembolism. 3 Nevertheless, postoperative hemorrhage is associated with significant morbidity and confers a high risk of wound necrosis. Therefore, in the outpatient clinic, we actively elicit a history of aspirin intake from all patients scheduled for surgery. Those taking the drug are fully informed of the associated hemorrhagic risk, and only if aspirin is being taken for its cardiovascular protective effect do we advocate its continuation. Surgery is preferably scheduled in the morning, meticulous hemostasis is secured before skin closure, and the wound is closely monitored in the recovery unit, with external pressure used, if necessary, to control minor oozing of blood. Once the wound is dry for at least 2 hours, the patient is discharged with careful instructions to remain vigilant for hemorrhage and hematoma. Patients taking aspirin who undergo local flap reconstruction incur an exponential increase in hemorrhagic risk compared with those with neither risk factor. Therefore, in this subgroup, it may be prudent to withhold aspirin during the perioperative period. The absence of robust studies examining the safety of temporary discontinuation of aspirin 3 precludes definitive recommendations, and urgent studies on this subject are warranted. Alternate options such as simplifying the repair or using skin grafts may be considered, but at the cost of an inferior cosmetic result. Conservative treatment of postoperative hemorrhage is associated with a high incidence of wound necrosis (Table 4). Therefore, we now have a low threshold for returning patients with postoperative hemorrhage for surgical reexploration, and urgently return every patients with flap reconstruction and hematoma in an attempt to salvage the flap. CONCLUSIONS Aspirin intake at the time of surgery to resect cutaneous head and neck lesions confers a small but statistically increased risk of postoperative hemorrhage. This risk is particularly pronounced in patients undergoing local flap reconstruction. Limited data also suggest that, in patients with flap repair who develop postoperative hematoma, failure to surgically reexplore the wound results in flap necrosis, and that aspirin does not protect against flap necrosis and, therefore, its role in minimizing microvascular thrombosis and improving local flap survival is questionable. Submitted for Publication: March 5, 2006; final revision received May 10, 2006; accepted July 20, Correspondence: Muthuswamy Dhiwakar, MS, MRCS, Department of Otolaryngology Head and Neck surgery, Raigmore Hospital, Inverness, Scotland IV2 3UJ (dhiwamahi@yahoo.com). Author Contributions: Dr Dhiwakar had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dhiwakar and McClymont. Acquisition of data: Dhiwakar and Khan. Analysis and interpretation of data: Dhiwakar. Drafting of the manuscript: Dhiwakar. Critical revision of the manuscript for important intellectual content: Khan and McClymont. Statistical analysis: Dhiwakar. Administrative, technical, and material support: Khan. Study supervision: Dhiwakar and McClymont. Financial Disclosure: reported. Acknowledgment: We thank Joanne MacPherson and Durga P. Dhiwakar, MBBS, for data compilation. REFERENCES 1. Bath FJ, Bong J, Perkins W, Williams HC. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2003;2:CD Shahar E, Folsom AR, Romm FJ, et al. Patterns of aspirin use in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 1996; 131: Burger W, Chemnitius JM, Kneissl GD, Rucker G. Low-dose aspirin for secondary cardiovascular prevention: cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation; review and meta-analysis. J Intern Med. 2005;257: Collins GL, Nickoonahand N, Morgan MB. Changing demographics and pathology of nonmelanoma skin cancer in the last 30 years. Semin Cutan Med Surg. 2004;23: Otley CC, Fewkes JL, Frank W, Olbricht SM. Complications of cutaneous surgery in patients who are taking warfarin, aspirin, or nonsteroidal antiinflammatory drugs. Arch Dermatol. 1996;132: Billingsley EM, Maloney ME. 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