BREAST Effects of Nitroglycerin Ointment on Mastectomy Flap Necrosis in Immediate Breast Reconstruction: A Randomized Controlled Trial Perry Gdalevitch, M.D., M.Sc. Nancy Van Laeken, M.D. Seokjae Bahng, B.Sc. Adelyn Ho, M.D. Esta Bovill, M.D., Ph.D. Peter Lennox, M.D. Penelope Brasher, Ph.D. Sheina Macadam, M.D., M.S. Vancouver, British Columbia, Canada

T

Background: Mastectomy flap necrosis is a common complication of immediate breast reconstruction that impacts recovery time and reconstructive success. Nitroglycerin ointment is a topical vasodilator that has been shown to improve skin flap survival in an animal model. The objective of this study was to evaluate whether the application of nitroglycerin ointment to the breast skin after mastectomy and immediate reconstruction causes a decrease in the rate of mastectomy flap necrosis compared with placebo. Methods: This study was conducted as a randomized controlled trial and included patients aged 21 to 69 years undergoing mastectomy and immediate breast reconstruction at the University of British Columbia–affiliated hospitals (Vancouver, British Columbia, Canada). Patients with a medical history that precluded the administration of nitroglycerin were excluded from the study. The target sample size was 400 patients. Nitroglycerin ointment (45 mg) or a placebo was applied to the mastectomy skin at the time of surgical dressing. Results: The trial was stopped at the first interim analysis after 165 patients had been randomized (85 to the treatment group and 80 to the placebo group). Mastectomy flap necrosis developed in 27 patients (33.8 percent) receiving placebo and in 13 patients (15.3 percent) receiving nitroglycerin ointment; the between-group difference was 18.5 percent (p = 0.006; 95 percent CI, 5.3 to 31.0 percent). Postoperative complications were similar in both groups [nitroglycerin, 22.4 percent (19 of 85); placebo, 28.8 percent (23 of 80)]. Conclusions: In patients undergoing mastectomy and immediate reconstruction, there was a marked reduction in mastectomy flap necrosis in patients who received nitroglycerin ointment. Nitroglycerin ointment application is a simple, safe, and effective way to help prevent mastectomy flap necrosis.  (Plast. Reconstr. Surg. 135: 1530, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

he blood supply to the breast skin comes from the underlying breast gland and from the dermal and subdermal plexuses of the

From the Division of Plastic and Reconstructive Surgery, University of British Columbia. Received for publication August 30, 2014; accepted November 19, 2014. This trial is registered under the name “The Effect of Nitroglycerin Ointment on Mastectomy Flap Necrosis,” ClinicalTrials.gov registration number NCT01608880 (https:// clinicaltrials.gov/ct2/show/NCT01608880). Presented at the University of British Columbia 32nd Annual Plastic Surgery Research Day, in Vancouver, British Columbia, Canada, April 11, 2014; and the 68th Annual Meeting of the Canadian Society of ­Plastic Surgeons, in Montreal, Quebec, Canada, June 24 ­ through 28, 2014. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001237

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skin.1 During mastectomy, the blood supply to the skin is compromised, which may lead to areas of superficial or full-thickness mastectomy flap necrosis (Fig. 1). These areas become obvious in the first postoperative week and can lead to prolonged recovery, delay in adjuvant treatments, and an unsatisfactory reconstructive outcome.2,3 Mastectomy flap necrosis is a frequent complication, occurring in 18 to 30 percent of patients undergoing mastectomy and immediate reconstruction.2–5 The incidence of this complication has increased with techniques such as nipple-sparing mastectomies and direct-to-implant reconstruction, which have become common practice in many centers.6–8 Other risk factors for developing Disclosure: None of the authors has any disclosures.

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Volume 135, Number 6 • Nitroglycerin Ointment and Flap Necrosis

Fig. 1. Superficial (left) and full-thickness (right) mastectomy flap necrosis.

this complication are well described and include increasing age (>65 years), obesity (body mass index >30), large breast size (mastectomy weight >800 g), Wise-pattern incision, previous radiation therapy, and active smoking.9–13 Prevention of mastectomy flap necrosis is dependent on the surgeon’s intraoperative clinical judgment as he or she evaluates mastectomy skin that needs to be excised. Laser-assisted indocyanine green dye angiography (SPY Elite; Novadaq, Bonita Springs, Fla.) is an intraoperative tool introduced recently that may help determine areas of decreased perfusion, thereby allowing the surgeon to excise these more accurately.14 Although SPY Elite has been shown to be highly sensitive and specific, it is an expensive tool not readily available outside of large centers.15 A recent cost analysis showed that the use of SPY for prevention of mastectomy flap necrosis is only cost effective if used in high-risk patients (e.g., body mass index >30, smokers, mastectomy weight >800 g).16 An ideal preventative measure for mastectomy flap necrosis would be simple, inexpensive and easy to administer. Nitroglycerin ointment is a potent topical vasodilator that increases local blood flow to the skin by dilating both arteries and veins.17 It has been shown to enhance skin flap survival in an animal model following frequent application of 2% nitroglycerin ointment.18 First described for the management of angina pectoris, nitroglycerin ointment is currently being used to aid in the healing of anal fissures, pressure sores, and peripheral tissue ischemia in neonates.17,19–22 In 1993, Fan et al. prospectively evaluated the

effect of a single dose of postoperative nitroglycerin ointment (1 ml, 5 mg) on the skin flaps of patients undergoing radical mastectomy (without reconstruction) and found that nitroglycerin application significantly reduced the mastectomy flap necrosis rate from 60 percent (24 of 40 control patients) to 19 percent (8 of 42 nitroglycerintreated patients) without any side effects.23 In 2010, in a large randomized trial (>6000 patients), Kutun et al. evaluated the effectiveness of a nitroglycerin transdermal patch [Nitroderm (Novartis, Basel, Switzerland), 50 mg, 8 hours/day for 5 days] on the skin flaps of patients undergoing modified radical mastectomy without reconstruction and found a significant reduction (39.5 percent versus 9.3 percent) in mastectomy flap necrosis with minimal side effects (headache in 10 percent of patients, similar to the control group).24 Despite this evidence, nitroglycerin ointment is not currently being used to prevent mastectomy flap necrosis, and there are no studies evaluating the effect of nitroglycerin ointment on mastectomy flap necrosis rates in patients undergoing mastectomy with immediate reconstruction. The primary objective of this study was to evaluate whether a single postoperative application of nitroglycerin ointment [Nitro-Bid 2% (E. Fougera & Co., a division of Nycomed U.S., Inc., Melville, N.Y.), 45 mg] decreases the rate of mastectomy flap necrosis in patients undergoing mastectomy with immediate breast reconstruction compared with patients receiving placebo. Secondary objectives included evaluating the effect of nitroglycerin ointment on the treatment received for mastectomy flap necrosis (dressings

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Plastic and Reconstructive Surgery • June 2015 and/or débridement and closure) and on early complications such as seroma, hematoma, infection, explantation, and capsular contracture.

PATIENTS AND METHODS The study was undertaken with the approval of the University of British Columbia Clinical Research Ethics Board (September 20, 2012). Permission for the off-label use of Nitro-Bid (nitroglycerin ointment 2%) was approved by Health Canada’s Therapeutic Products Directorate (August 29, 2012). Starting in December of 2012, all patients aged between 21 and 69 years that underwent skin-sparing or nipple-sparing mastectomy followed by immediate breast reconstruction at three university-affiliated centers were reviewed for study eligibility. Patients were recruited by participating surgeons (or their designate), and informed consent was obtained in the office or in the preoperative care unit on the morning of surgery. Patients with a medical history that precluded the administration of nitroglycerin were excluded from the study, including the following: history of cardiac insufficiency, hypotension, sensitivity to nitrites, severe liver impairment, glaucoma, hyperthyroidism, recent head trauma, severe anemia, or taking certain medications (i.e., alteplase, aspirin, beta-blocker, calcium channel blocker, diuretics, or thiazides).25 Sample Size Calculation We reviewed the mastectomy flap necrosis rate at our institution for the years 2008 to 2011, which varied from 10.5 to 38.3 percent. Assuming a 20 percent rate for the placebo group, and considering a clinically significant rate reduction of 50 percent, a sample size of 200 patients per arm for a total of 400 patients was calculated (α = 0.05, two-sided; β = 0.20). A single interim efficacy analysis was planned after 50 percent of patients had been accrued. A Haybittle-Peto ­stopping ­boundary (p < 0.001) was to be used. Data Collection Preoperative, operative, and postoperative case report forms were created for the purpose of prospective data collection and were completed by the surgeon. The following information was collected on the preoperative case report form: date of birth, body mass index, smoking status, pathology, history of biopsy or lumpectomy, radiation exposure, chemotherapy exposure, hormonal treatment, medical comorbidities, breast measurements including bra size, breast ptosis, and previous scars.

The following information was collected on the operative case report form: dates and details of the surgical interventions including general surgeon, plastic surgeon, use of local anesthetic, type of mastectomy, laterality, size of mastectomy specimen, lymph node sampling, type/size of alloplastic device, acellular dermal matrix size and thickness, autologous flap details, mastectomy incision, and mastectomy flap thickness score. The following information was collected on the postoperative case report forms at every postoperative visit: timing of drain removal; early complications such as infection, seroma, and hematoma; the presence and details of mastectomy flap necrosis (e.g., superficial or full thickness; location and size; treatment); and need for postoperative chemotherapy, radiation therapy, or hormonal treatment. Randomization and Ointment Application A senior statistician at the Centre of Clinical Epidemiology and Evaluation at the University of British Columbia created the randomization sequence using the Stata 11.0 software package (StataCorp LP, College Station, Texas). The randomization was stratified by a staff surgeon, and permuted blocks of varying size were used. The randomization list was provided to a research coordinator who was not involved in patient recruitment or treatment. No other person had access to the randomization list. Nitroglycerin ointment (Nitro-Bid 2%) was used in its original 60-g packaging to avoid issues related to contamination, impurities, and stability as required by Health Canada. The placebo was prepared by a university-affiliated pharmacist and consisted of an inert compound made from white petrolatum, anhydrous lanolin, and emollient cream and was identical in color and consistency to nitroglycerin ointment. Both ointment tubes were then circumferentially covered with duct tape to blind the surgeon, patient, and research team. An ointment tube provided approximately 20 doses per 60 g of tubing. At the time of surgery, the research coordinator consulted the randomization list for the next treatment allocation and delivered the study drug to the operating room. Mastectomy was performed by the University of British Columbia general surgeons using electrocautery, followed by reconstruction by five plastic surgeon members of the breast reconstruction program. A thin layer of ointment was applied at the time of surgical dressing by the attending plastic surgeon concentrically from the center of the breast to the periphery at a dose of 45 mg of

1532 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Volume 135, Number 6 • Nitroglycerin Ointment and Flap Necrosis nitroglycerin ointment (equivalent to 7.5 cm on the measuring strip) (Fig. 2). The ointment and dressing were left in place for a minimum of 48 hours. In patients undergoing bilateral breast reconstruction (often with one side undergoing prophylactic mastectomy), only the mastectomy performed by the general surgeon (therapeutic mastectomy) received the study drug to avoid the potential of an increased effect of the nitroglycerin ointment from the contralateral breast. All patients were admitted to the hospital postoperatively for a minimum of 24 hours. Interim Analysis On February 24, 2014, after 165 patients had been randomized, the interim analysis was conducted. All randomized patients were included in the analysis in the group to which they were allocated (intention-to-treat). The interim report was sent to two independent plastic surgeons outside our institution for independent review. Based on the findings of the interim report, the study was stopped early for proof of efficacy. Statistical Analysis To describe the patient population, descriptive statistics were generated for baseline variables by treatment group. Continuous variables were summarized with mean ± SD or median (10th and 90th percentiles) if the data were skewed. Categorical variables were summarized with frequency (percent). Pearson chi-square test was used for between-group comparisons of proportions. Point and interval estimates were calculated for between-group differences. We also performed a

Fig. 2. Nitro-Bid measuring strip for dosing the study ointment (7.5  cm). (From Paladin Labs, Inc. Product monograph: Nitrol 2%. Available at: http://paladin.lateshowlabs.com/wp-content/ uploads/PM-approved_Nitrol_14Apr2009_CN128917_V2.0_ EN.pdf. Accessed January 12, 2015.)

secondary analysis adjusting for known risk factors for mastectomy flap necrosis. These factors were determined a priori based on literature review and surgeon experience and included age older than 65 years, body mass index greater than 30, active smoking, history of preoperative radiation therapy, mastectomy weight greater than 800 g, Wise-pattern incision, nipple-sparing mastectomy, and direct-to-implant reconstruction.5–13 We also performed an exploratory analysis of whether the effect of nitroglycerin varied according to the number of risk factors. A score of 1 was given for each of the aforementioned risk factors. A total risk score was calculated as the sum of the eight scores. All analyses were performed using Stata 11.0, and all tests are two-sided.

RESULTS One hundred sixty-five patients participated in the study, with 85 randomized to the nitroglycerin ointment arm and 80 randomized to the placebo arm. Of the 85 patients in the treatment arm, one patient did not receive the allocated ointment and two patients had the ointment wiped off in the recovery room without unblinding because of hypotension. There were no patients lost to followup, and all randomized patients were included in their allocated group (Fig. 3).26,27 Patient demographics and baseline characteristics were similar between the treatment and placebo group (Table 1), as were breast baseline characteristics (Table 2) and operative characteristics (Table 3). All patients had a minimum of 27 days’ follow-up, a period sufficient for the development of mastectomy flap necrosis. Mastectomy flap necrosis occurred in 24.2 percent (40 of 165) of cases in this cohort. Mastectomy flap necrosis was less likely in the group receiving the nitroglycerin ointment [15.3 percent (13 of 85)] versus the placebo [27 of 80 (33.8 percent); p = 0.006] (Table 4). The difference in mastectomy flap incidence between the treatment and placebo groups was 18.5 percent (95 percent CI, 5.3 to 31 percent). The effect was consistent across severity of necrosis. The difference in the rate of necrosis was reflected in decreased rates of débridement and closure of the wound (Table 4). Explantation of an alloplastic device because of mastectomy flap necrosis occurred in 2.4 percent of cases (four of 165), two patients in each group. A secondary analysis adjusting for body mass index greater than 30, age older than 65 years, active smoker, preoperative radiation therapy, mastectomy

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Plastic and Reconstructive Surgery • June 2015

Fig. 3. Consolidated Standards of Reporting Trials flow diagram. BP, blood pressure. (From Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomized trials. Ann Intern Med. 2010;152:726–732; and Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trial. BMJ 2010;340:c869.)

weight greater than 800 g, Wise-pattern incision, direct-to-implant reconstruction, and nipple-sparing mastectomy yielded a similar estimated difference of 17.5 percent (95 percent CI, 5.0 to 30.0 percent). An exploratory analysis looking at the effect of nitroglycerin ointment on different risk factor groups was also performed (Table 5). The total risk factor score ranged from 0 to 4. Because of small numbers, we combined categories 3 and 4. As expected, the risk of mastectomy flap necrosis in the placebo group increased with increasing score. The observed risk of mastectomy flap necrosis was lower in the nitroglycerin group in all risk categories. Early complications such as seroma, hematoma, infection, and early capsular contracture occurred in 25.5 percent of patients (42 of 165)

and were similar in both groups (Table 6). The most common early complication was seroma, which occurred in 12.7 percent of patients (21 of 165). Severe headache was reported in 2.4 percent of patients (two of 85) receiving nitroglycerin ointment compared with 0 percent in the placebo group. Hypotension was reported in two patients who received the nitroglycerin ointment. In both cases, the hypotension did not resolve with removal of the study ointment and was likely attributable to other factors. The results of the interim analysis did not meet the prespecified stopping boundary (i.e., p ≤ 0.001). However, given the large reduction in the rate of mastectomy flap necrosis in the nitroglycerin group, the investigators were no

1534 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Volume 135, Number 6 • Nitroglycerin Ointment and Flap Necrosis Table 1.  Patient Demographics in the Placebo- and Nitroglycerin-Treated Groups Demographics Age, yr  Mean ± SD  Median  P10–P90 Body mass index, kg/m2  Mean ± SD  Median  P10–P90 Laterality, no. (%)  Unilateral  Bilateral Smoking, no. (%)  Never  Active  Former Diabetes, no. (%) Hypertension, no. (%) Genetic predisposition,   no. (%)   BRCA1 gene carrier   BRCA2 gene carrier  Missing Preoperative chemotherapy, no. (%) Preoperative hormonal therapy, no. (%)

Placebo (n = 80)

Nitroglycerin (n = 85)

49.9 ± 9.7 49.0 37.5–62.5

50.0 ± 9.2 49.0 39.0–63.0

24.0 ± 4.9 22.6 20.1–30.7

24.9 ± 4.6 23.8 19.9–31.6

45 (56.3) 35 (43.7)

44 (51.8) 41 (48.2)

64 (80.0) 2 (2.5) 14 (17.5) 2 (2.5) 11 (13.8)

67 (78.8) 0 (0.0) 18 (21.2) 0 (0.0) 8 (9.4)

2 (2.5) 1 (1.3) 1

1 (1.2) 1 (1.2) 1

25 (31.2)

23 (27.1)

5 (6.3)

12 (14.1)

P10–P90, 10th to 90th percentile.

longer in the state of personal equipoise and felt it unethical to continue to randomize patients. A conditional power calculation was performed; the probability of detecting a significant benefit for nitroglycerin should the trial continue to completion with an assumed mastectomy flap necrosis rate of 25 percent (the observed rate) in both arms was 82 percent.

DISCUSSION To our knowledge, this is the first randomized trial evaluating the use of nitroglycerin ointment in the prevention of mastectomy flap necrosis in patients undergoing mastectomy and immediate reconstruction. Our study showed that the application of a single 45-mg dose of nitroglycerin ointment at the time of the surgical dressing reduced the incidence of mastectomy flap necrosis by more than half. The absolute risk reduction of 18.5 percent translates to a number needed to treat of 5.4. In patients treated with nitroglycerin ointment, we also found an approximate 50 percent reduction in full-thickness mastectomy flap necrosis, which translates to a similar reduction in cases requiring surgical débridement and closure. In addition, after stratifying patients into risk factor subgroups, the observed reduction in mastectomy flap necrosis prevailed in all risk categories

Table 2.  Breast Characteristics in the Placebo- and Nitroglycerin-Treated Groups Breast Characteristics Reason for mastectomy,   no. (%)  Prophylactic  Therapeutic Pathologic condition, no. (%)  Benign (prophylactic)  Ductal carcinoma in situ  Invasive ductal carcinoma  Invasive lobular carcinoma  Other Radiation therapy, no. (%) Previous lumpectomy, no. (%) Breast size (cup size), no. (%)  A  B  C  D  Larger than D Breast width, cm  Mean ± SD  Median  P10–P90 Breast ptosis, no. (%)  1  2  3  4 Previous scar, no. (%)  None  Biopsy  Lumpectomy  Reduction or mastopexy

Placebo (n = 80)

Nitroglycerin (n = 85)

10 (12.5) 70 (87.5)

4 (4.8) 80 (95.2)

10 (12.5) 13 (16.3) 54 (67.5) 3 (3.8) 0 (0.0) 7 (8.8) 24 (30.0)

4 (4.7) 21 (24.7) 54 (63.5) 4 (4.7) 2 (2.6) 9 (10.6) 29 (34.1)

12 (15.0) 30 (37.5) 19 (23.8) 10 (12.5) 9 (11.2)

10 (11.8) 32 (37.7) 18 (21.2) 13 (15.3) 12 (14.2)

13.8 ± 1.8 13.5 12.0–16.0

14.0 ± 1.8 14.0 12.0–16.0

26 (32.5) 39 (48.8) 12 (15.0) 3 (3.8)

28 (32.9) 32 (37.7) 17 (20.0) 8 (9.4)

36 (45.0) 17 (21.3) 24 (30.0) 3 (3.7)

43 (50.6) 15 (17.7) 27 (31.8) 0 (0.0)

P10–P90, 10th to 90th percentile.

in patients treated with nitroglycerin. Given the small number of patients and events in each subgroup, we were unable to determine definitively whether the treatment effect might increase (or decrease) with increasing risk factors. Overall, these findings suggest that nitroglycerin ointment increases perfusion to the traumatized skin flap, thereby reducing the occurrence of flap necrosis in this patient population. The mechanism of action of topical nitroglycerin occurs through smooth muscle relaxation in the vessel wall, thereby promoting both a venous and arterial dilation.17 Endothelium-dependent vessel relaxation impairment is important to the development of skin flap necrosis, a process that may be mitigated by nitroglycerin or other nitric oxide donors.28 Nitroglycerin may also induce endothelial cells to synthesize prostacyclin, a known vasodilator and inhibitor of platelet aggregation, which may contribute to flap survival by decreasing thrombosis of smaller vessels.29 Nitroglycerin ointment was first studied in an animal model by Rohrich et al. in 1984 and was found to significantly increase axial pattern skin

1535 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Plastic and Reconstructive Surgery • June 2015 Table 3.  Operative Factors in the Placebo- and Nitroglycerin-Treated Groups Operative factors Local anesthetic, no. (%)  None  0.25% Marcaine* with  epinephrine  0.25% Marcaine* without  epinephrine Reconstruction type, no. (%)  Alloplastic    Direct-to-implant    First-stage tissue  expander   Acellular dermal matrix   and tissue expander  Autologous   Pedicled TRAM flap   Deep inferior epigastric  perforator    Latissimus dorsi Incision type, no. (%)  Skin-sparing mastectomy    Horizontal ellipse    Vertical ellipse    Wise pattern    Other  Nipple-sparing mastectomy   Periareolar and radial   lateral extension   Lateral incision only    Vertical incision    Inframammary fold  incision    Other Sentinel lymph node biopsy,   no. (%) Axillary lymph node dissection Flap thickness, no. (%)  Significant dermal  exposure  Patches of dermis exposed  Thick flap without dermis  exposed  Moderately thick  Very thick  Missing Mastectomy weight, g  Median  Range (P10–P90) Plastic surgeon, no. (%)  A  B  C  D  E Breast surgeon, no. (%)  X  Y  Z  Other

Placebo (n = 80)

Nitroglycerin (n = 85)

0 (0.0)

1 (1.2)

75 (83.8)

77 (90.6)

5 (6.2)

7 (8.2)

69 (86.2) 43 (53.8)

59 (69.4) 42 (49.4)

19 (23.8)

13 (15.3)

7 (8.8) 11 (13.8) 8 (10.0)

4 (4.7) 26(30.6) 14 (16.5)

3 (3.8) 0 (0.0)

9 (10.6) 3 (3.5)

60 (75.0) 24 (30.0) 5 (6.3) 31 (38.8) 0 (0.0) 20 (25.0)

61 (71.8) 30 (35.3) 2 (2.4) 28 (33.9) 1 (1.2) 24 (28.2)

8 (10.0) 1 (1.3) 2 (2.5)

14 (16.5) 1 (1.2) 1 (1.2)

9 (11.3) 0 (0.0)

6 (7.1) 2 (2.4)

44 (55.0)

47 (55.3)

15 (18.8)

13 (15.3)

3 (4.2) 17 (23.9)

3 (4.3) 12 (17.1)

30 (42.3) 16 (22.5) 5 (7.0) 9

31 (44.3) 23 (32.9) 1 (1.4) 15

479.5 222–1100

497.0 160–1137

2 (2.5) 9 (11.3) 40 (50.0) 8 (10.0) 21 (26.3)

9 (10.6) 10 (11.8) 48 (56.5) 12 (17.1) 6 (7.1)

23 (28.8) 23 (28.8) 21 (26.2) 13 (16.2)

26 (30.6) 26 (30.6) 16 (18.8) 17 (20.0)

TRAM, transverse rectus abdominis muscle; P10–P90, 10th to 90th percentile. *Hospira, Inc., Lake Forest, Ill.

flap survival in both rats (89.4 percent versus 68.9 percent flap area survival) and pigs (74.1 percent versus 50.5 percent flap area survival) when a

30-mg dose was applied preoperatively and every 6 hours for 3 days.18 In 1985, Nichter et al. studied the effects of nitroglycerin transdermal pads on random pattern flaps in rats using a 5-mg daily dose for 2 weeks. They did not show a difference in flap survival compared with controls, but this may have been attributable to the much smaller daily dose or the transdermal delivery used in their protocol.30 Nitroglycerin ointment was first used on skin flaps in humans 1 year later in a trial on the penile flaps of children undergoing hypospadias repair and was found to improve flap survival.31 Nitroglycerin ointment has also been studied in comparison with other vasodilating agents such as enteral phenoxybenzamine, enteral nifedipine, and intravenous allopurinol and was found to be superior in treating failing random pattern skin flaps in rats.32,33 The most substantial animal study looking at the effect of nitroglycerin on random pattern skin flaps included 61 rats randomized to one of six topical treatment groups, treated immediately postoperatively and every 6 hours for 1 week. Although topical nitroglycerin alone improved flap survival, the combination of topical nitroglycerin and topical trolamine salicylate showed the greatest capacity for flap salvage.34 Although the majority of animal studies have shown increased flap survival with the use of nitroglycerin ointment, three studies have shown a lack of benefit.31,35,36 In all of these studies, the dose of nitroglycerin used was low (5 mg), which may be the reason a significant effect was not detected. The doses used in previous clinical studies on nitroglycerin and mastectomy flaps ranged from a single 5-mg application to a 50-mg transdermal daily protocol for 5 days.23,24 The dose used in this study (45 mg, 3 inches) was determined using these previous studies as a guideline and by consulting an academic cardiologist. We selected a single 45-mg dose to keep the protocol simple yet effective and allow for patient monitoring in the case of adverse events. This dose was applied to a single breast, and caution should be exercised in treating both breasts. Either doubling the dose or splitting the dose over a larger surface area may have greater effects on a patient’s blood pressure. In this study the overall incidence of mastectomy flap necrosis in the placebo group was higher than we had estimated (33.8 percent), but similar to rates in the literature.37,38 This rate is also consistent with the significant rise in mastectomy flap necrosis at our institution since the adoption of nipple-sparing mastectomy and direct-to-implant reconstruction. Despite the higher risk of mastectomy flap necrosis, these

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Volume 135, Number 6 • Nitroglycerin Ointment and Flap Necrosis Table 4.  Mastectomy Flap Necrosis in the Placebo- and Nitroglycerin-Treated Groups Placebo (n = 80) Mastectomy flap necrosis, n (%)   Superficial thickness   Full thickness Treatment Débridement and closure   Under local anesthetic   Under general anesthetic Dressings Explantation (loss of tissue expander/implant)

Nitroglycerin (n = 85)

95% CI for Difference

p

27 (33.8) 9 (11.2) 18 (22.5)

13 (15.3) 5 (5.9) 8 (9.4)

5.3–31.0

0.006

1.9–24.3

0.021

16 (20.0) 11 (13.7) 5 (6.3) 27 (33.8)

8 (9.4) 3 (3.5) 5 (5.9) 13 (15.3)

0.0–21.6

0.054

2 (2.5)

2 (2.4)

newer techniques allow for better aesthetic outcomes, often in a single stage, and are therefore preferred by patients and surgeons. The complications seen in this cohort were consistent with previous studies.38,39 There was a small decrease in overall complication rates in the treatment versus placebo group (22.4 percent versus 28.8 percent). Explantation of a prosthetic device because of mastectomy flap necrosis occurred rarely (2.4 percent) so that a significant reduction of this complication could only possibly be detected in a much larger cohort. Severe headache was reported in two patients in the treatment arm and is a possible side effect of the nitroglycerin ointment. Hypotension did occur in two patients who received the nitroglycerin ointment but was likely caused by pain medication Table 5.  Mastectomy Flap Necrosis Risk Factor Score and Mastectomy Flap Necrosis Rates in the Placebo and Nitroglycerin-treated Groups* MFN Risk Factor Score

No.

Nitroglycerin Risk (%) Ratio

Placebo (%)

0 28 2/14 (14.3) 1 37 5/18 (27.8) 2 72 12/33 (36.4) 3 or 4 20 and 8 8/15 (53.3)

1/14 (7.14) 1/19 (5.3) 8/39 (20.5) 3/13 (23.1)

0.50 0.19 0.56 0.43

95% CI 0.05–4.9 0.02–1.47 0.26–1.21 0.14–1.30

MFN, mastectomy flap necrosis. *Mantel-Haenszel test of homogeneity, p = 0.80.

Table 6.  Complication Rates in the Placebo- and Nitroglycerin-Treated Groups Placebo (%) No. Any complication* Seroma Infection Hematoma Explantation Other  Hypotension  Headache

80 23 (28.8) 12 (15.0) 5 (6.3) 3 (3.8) 2 (2.5) 2 (2.5) 0 (0.0) 0 (0.0)

*p = 0.35; 95% CI for difference, −6.9–19.5.

Nitroglycerin (%) 85 19 (22.4) 9 (10.6) 3 (3.5) 2 (2.4) 3 (3.5) 6 (7.0) 2 (2.4) 2 (2.4)

and underresuscitation, as the hypotension persisted after removal of the ointment. Headache and hypotension remain possible complications of nitroglycerin ointment, and patient blood pressure should be monitored in the immediate postoperative setting. The strengths of this study include the randomized controlled trial design, blinded ointment allocation, nearly perfect adherence to treatment allocation, and the 100 percent follow-up rate. In addition, our findings are generalizable to most breast cancer patients, although caution is advised in older patients and patients on antihypertension medication, who may be more sensitive to nitrates. These patients were excluded from the study but have since been treated routinely with nitroglycerin ointment without any adverse events. A limitation of this study is that it was conducted at a single center, although three different sites were involved. Mastectomy flap necrosis is a multifactorial complication that varies greatly depending on the institution. Centers with lower rates of mastectomy flap necrosis may not see as drastic an effect with nitroglycerin ointment. However, given the simplicity and low complication profile of the intervention, it remains a simple addition to other preventative measures. Further studies are needed to determine the appropriate dose for each breast in treating bilateral mastectomy skin. Clinical studies are also needed to help elucidate whether repeated application or a combination topical ointment (e.g., nitroglycerin/trolamine/ salicylate) could further reduce mastectomy flap necrosis rates.

CONCLUSIONS The single application of nitroglycerin ointment (45 mg, 3 inches) to the breast skin in patients undergoing mastectomy with immediate reconstruction decreased the incidence of mastectomy flap necrosis by half (from 33.8 percent to 15.3 percent) with a number needed to treat

1537 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Plastic and Reconstructive Surgery • June 2015 of 5.4. Nitroglycerin ointment application on mastectomy flaps is a simple, readily available, and affordable ($3) measure to prevent mastectomy flap necrosis. In high-risk patients, it can be combined with other modalities to optimize patient outcomes. The authors propose that a simple and cost-effective approach to the prevention of mastectomy flap necrosis would include the application of nitroglycerin on all patients undergoing mastectomy with immediate reconstruction. Perry Gdalevitch, M.D., M.S. Division of Plastic and Reconstructive Surgery University of British Columbia 5951 Oak Street Vancouver, British Columbia V6M 2W1, Canada [email protected]

ACKNOWLEDGMENTS

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1539 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Effects of nitroglycerin ointment on mastectomy flap necrosis in immediate breast reconstruction: a randomized controlled trial.

Mastectomy flap necrosis is a common complication of immediate breast reconstruction that impacts recovery time and reconstructive success. Nitroglyce...
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