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Skin cancer surgery on referral

Randomized control trial of ointment

Prospective trial of mupirocin versus paraffin versus no ointment

Anthony J. Dixon, MBBS FACRRM FACSCM

Mary P. Dixon, B Appl Sci (Nursing)

John B. Dixon, MBBS FRACGP PhD

Abstract

Background: A blinded randomized clinical trial was undertaken to evaluate the effect of applying ointment to a wound before occlusive dressing in comparison with no ointment or sterile paraffin.

Methods: Some 778 patients with 1801 surgical wounds following excision of skin lesions were enrolled in the trial. No ointment was placed on 510 sutured wounds of 247 patients, paraffin ointment was put on 729 wounds (269 patients) and mupirocin ointment on 562 wounds (262 patients). Wound infection, scar, haemorrhage, dehiscence and other complications were assessed at suture removal. At 6-9 months after surgery, patients were surveyed to assess the wounds, with a response rate of 74%.

Results: There were no significant differences in outcome for all end points evaluated. The infection rate was 1.4 % with no ointment, 1.6 per cent for paraffin and 2.3 per cent for mupirocin (P =0.490) Total complication rates were 3.5, 4.7 and 4.8 per cent for no ointment, paraffin and mupirocin respectively (P =0.590). Some 10.9, 10.3 and 8.2 per cent of patients respectively had a neutral or negative perception of their wounds at 6-9 months after surgery (P =0.650), There was no difference in postoperative pain, degree of inconvenience, overall level of satisfaction with treatment.

Conclusion: Putting ointment on a surgical wound before occlusive dressing does not benefit the patient. In view of the risk of antibiotic resistance, mupirocin ointment is not indicated for clean surgical wounds.

Introduction

Ointment is often placed under an occlusive dressing after the excision and closure of a skin lesion 115, 116, 159, 166 in the belief that it improves the aesthetic outcome and that antibiotic ointment may reduce the incidence of wound infection. An infection rate of 2 - 5 per cent may be expected for uncontaminated wounds following skin lesion excision 64, 119 with higher rates below the knee and in the groin78, 167. A number of topical antimicrobial and antiseptic preparations are available, 168, 169 but there is little evidence to support their use on uncontaminated surgical wounds.

Mupirocin ointment is considered to be an effective and safe topical bactericidal antibiotic170 that results in a reduced postoperative infection rate when used on contaminated lesions before excision.166 It is as effective as oral antibiotics in the prevention and treatment of superficial skin infections170, 171 and compares favorably with oral antibiotics for the management of post excisional and experimental skin infections70, 131. Although these favorable effects cannot be extrapolated to the prevention of infection in non-contaminated wounds, mupirocin is widely advocated for clean wounds to reduce infection rates.115, 166

Mupirocin resistance has been observed in methicillin-resistant Staphylococcus aureus (MRSA) isolates 172 ,and  a high  incidence of mupirocin MRSA resistance has been reported in Malaysia133. Mupirocin has a role in interrupting the colonization of MRSA in affected patients, including preoperative surgical patients173, but continuing  widespread usage may reduce its effectiveness in this respect.174 175

Moist occlusive dressings are used routinely by the authors after excising skin lesions as they have been reported to improve healing and to result in fewer infections and other complications.120, 130, 158, 160, 175-177

A blinded randomized controlled study was undertaken to determine whether the use of ointment, ointment containing an antibiotic (mupirocin), or no ointment under occlusive dressings would reduce the incidence of infection and other wound complications in patients with non-contaminated surgical wounds. Effects on patient comfort and long-term satisfaction with the appearance of the healed wound were also investigated.

Methods

The trial was conducted in accordance with the Declaration of Helsinki and approved by Barwon Health Research & Ethics Committee. All patients gave signed informed consent.

From the authors’ previous experience, an infection rate of approximately 4 per cent might be expected; a reduction to less than 1% would be clinically significant. It was determined that  500 surgical wounds in each of the three groups would provide an 80 per cent likelihood of detecting  a four-fold difference in the incidence of infection between the antibiotic ointment group and the control group receiving  no ointment or paraffin (alpha of 0.05). Recruitment therefore continued until at least 500 surgical wounds were represented in each treatment group. Individual wound repairs in the same patient were treated as independent events, whether performed synchronously or at a different time (up to 15 lesions per patient were permitted, to avoid overrepresentation of some individuals).

Newly referred patients who attended the Skincanceronly clinic between July 1st 2002 and December 31st 2003 (when sufficient numbers had been recruited) were invited to participate. Inclusion criteria were: patient aged 18 years or more, eligible to give informed consent and able to comply with treatment requirements; and presence of a skin lesion for which incisional or excisional surgery was deemed appropriate and that would result in a wound appropriately closed with interrupted polyamide sutures.

Patients were excluded if the skin was contaminated or infected before surgery, if the surgical site was not amenable to a moist occlusive dressing (eg. eyelid, lip), or if the patient had a known allergy to the occlusive dressing or one of the ointment preparations. Partial thickness skin graft donor sites were also excluded.

Patients (not wounds) were randomized prospectively to one of three groups before the placement of moist occlusive dressings: no ointment, sterile paraffin (Lacri-Lube®, Allergon, Urvine, CA, USA) and mupirocin ointment 20mg/gm (Bactroban®, GlaxoSmithKline, Middlesex, UK).

Allocation to a treatment group was undertaken by an independent person drawing one of 150 discs, (50 each of three different colours) from a barrel. Upon completing the barrel, the process was repeated. Neither surgeon nor patient was aware of randomization, although patients could not be completely blinded to the application of an ointment by the nursing staff.

One surgeon (A.J.D) performed all procedures. Surgical techniques included punch biopsy, elliptical excision, incisional biopsy, full and partial thickness skin grafts, and random pattern skin flaps. The site of all removed lesions was recorded and all specimens sent for histopathological examination. Where multiple tumours required excision, the most concerning lesion was excised first.120, 121

All patients were given a detailed postoperative instruction sheet regarding wound management, warning signs and details of return appointments. Patients were followed clinically until wound healing was completed at least until removal of sutures and longer following skin flap or graft surgery, or if a complication developed.

The primary outcome measure was the incidence of wound infection, which was recorded and classified as: purulent suture site, suture abscess, cellulitis, infective necrosis, large subcuticular abscess, regional lymphadenitis and septicaemia. When there was abscess formation or evidence of involvement beyond the local site, a wound swab was taken for culture; otherwise, the infection was assessed clinically. In the absence of suppuration, a wound was considered infected if three out of the following signs were present: discharge, pain, erythema or induration. All wound infections were treated with oral dicloxacillin, 500mg orally four times daily, unless sensitivity or allergy deemed this to be inappropriate.

Other complications were recorded for each wound managed. Adverse scar outcomes were classified as: wound spread, suture markings, suture reaction, hypertrophy, keloid, discoloration, hypo pigmentation, wound depression, wound elevation, dog ears, and contracture.

Other local adverse outcomes recorded were post operative bleeding, allergy to dressing, allergy to skin preparation, contact dermatitis, local recurrence, subcutaneous fibrosis, granuloma, dehiscence, pruritus, persistent pain and nerve damage, ectropion, nodal involvement and distant metastases.

Post operative pain was also recorded as: no pain, minimal discomfort not requiring analgesia, mild pain relieved with paracetamol, moderate pain requiring stronger analgesia, severe pain unrelieved by analgesia, worst pain ever experienced.

Questionnaire at 6-month follow-up

Six months after surgery each patient was posted a one-page survey to complete and return. Any patient not returning the survey was sent another, at 8 - 9 months after operation. The survey asked patients to rate the pain experienced and any inconvenience of the dressing, to comment on their experience, to assess the final aesthetic appearance of the first operated area as excellent, very good, good, fair, poor or very poor, and to rate the quality of the service. Each patient’s categorical scores were converted to ordinal variables for analysis as follows: excellent, 10, very good, 8, good, 6, fair, 4, poor, 2 and very poor, 0.

Patients who had undergone multiple procedures were asked to rate only the first procedure. A sub analysis of the first lesions excised was performed for patients who had multiple lesions during the same operation. Further, the survey sent to patients pertained only to the first lesion excised.

Statistical Analysis

Analysis was conducted on an intention to treat basis. Patient characteristics and differences between groups were assessed by means of analysis of variance using Tukey post-hoc analysis, Kuskall-Wallis H test and chi-square test as appropriate. All key outcome incidences were analyzed using the chi-square test and antibiotic ointment was compared with controls individually using 2 x 2 tables. All analysis was performed using SPSS version 12.0.1 (SPSS, Chicago, Illinois, USA.)

Results

Some 778 patients were recruited from a total of 926 referred to the clinic over the study interval who required therapy that involved surgical repair of incisions; 148 patients were excluded (figure1).

 Patient characteristics and numbers of incisions in each group are detailed in Table 1. One patient had more than 15 lesions treated and so only the first 15 were included within the study. There were no significant differences between the groups.

Each enrolled patient had a median of 1 (interquartile range of 1; range 1 – 15) surgical wounds managed over the 18-month study interval. Second and subsequent operations included surgery to different skin sites as well as some lesions (predominantly malignant melanoma) that were managed in two stages with two excisions and closure.

Some 69.4 per cent of wounds were closed with elliptical excisions and direct closure; 29.9 per cent of closures involved a random pattern skin flap, and  0.7%  a skin graft. There was no difference between groups.

Post operative complications

Complications per wound closed are detailed in Table 2. There was no difference in the number of total complications between groups (p= 0.590). Overall complication rates were 3.5 per cent in the no ointment group, 4.7 per cent for paraffin and 4.8 per cent for mupirocin. No patient experienced an allergic or other adverse reaction attributable to the ointment.

Infection

There was a total of 32 wound infections, giving an overall rate of 1.8 per cent, with no significant differences between the groups (p=0.490) (Table 2). Infections were predominantly suture abscesses and cellulitis. All wound infections responded to oral antibiotics, predominantly dicloxacillin. No abscess required drainage, and no infection necessitated intravenous antibiotics or patient hospitalization. No patient had more than one infected wound.

A sub-analysis of the excision region found a significant increase in the risk of wound infection in lower limb lesions. The 225 leg lesions had an infection rate of 4.4 per cent, compared with 1.4 per cent for other body areas (p<0.001), although the group to which the patient was randomized did not influence the risk of infection in the leg. (Table 2).

A sub-analysis of the first lesion on each of the 778 patients revealed no difference in the incidence of skin infection, wound problems, bleeding or total complications between the three groups. The rate of skin infection of first wounds was 1.6 per cent for no ointment, 3.3 per cent for paraffin and 2.3 per cent for mupirocin (p=0.460). The mean incidence of infection for first wounds was 2.3 per cent, and there was no statistically significant difference from the pooled data (not shown). Further sub-analysis of small excisions and skin flap closure also showed no differences between groups (data not shown).

Non-infective complications

There were fewer scar complications in the no-ointment group than when ointment was used, a difference that appeared to be due largely to an increased risk of skin necrosis in the mupirocin group (p=0.007) (Table 2). Of the seven cases of skin necrosis, five were in flaps and two in elliptical excisions, (one scalp and one ear).

Survey at 6-months

A total of 576 patients (74.0 per cent) returned the completed survey. Non responders were not significantly different to responders with regards age, sex, sites of wounds or complication rate (data not shown).

The application of ointment to the wound made no difference to the degree of wound pain or dressing discomfort experienced after excision (Table 3). Analgesics were used by 25.6, 29.7 and 25.3 of patients in the no-ointment, paraffin and mupirocin groups respectively (p=0.540). Few found their dressing disruptive, embarrassing or intolerable. (1.1, 2.5 and 2.6 per cent in the three groups respectively (p=0.540).

With regard to the appearance of the surgical scar at 6-9 months, there was no difference between patients in the three groups for any variable (Table 3). Patients who described their wound outcome as excellent, very good or good were grouped as positive wound responders. The incidence of neutral or negative scoring was 10.9, 10.3 and 8.2 per cent in the no-ointment, paraffin and mupirocin groups respectively (p=0.650), and 9.8 per cent overall.

Discussion

To the authors’ knowledge, no substantial evidence has been published regarding the value of applying ointment to clean surgical wounds after suturing. Current understanding of the role of antibiotic prophylaxis in skin cancer surgery has been reviewed by Maragh et al.114, and there is little evidence regarding the use of topical antibiotics.

This study has shown that paraffin and mupirocin ointment provide no additional benefit to the patient. Existing advice regarding the role of ointments on wounds116, 159, (largely antibiotic ointment) following skin lesion surgery and before dressing should  be reviewed in the light of these findings.

This study has limitations. The primary analysis was on wounds not patients, even though it was patients who were randomized. One wound per patient could have been studied, but this would have involved so many patients that the decision was taken to treat each wound as a separate event. The sub-analysis of the first wound treated in each patient did give the same findings, and no patient with several incisions had more than one infected wound.

All operations were performed by a single surgeon in a rural city in southern Australia, a region with a temperate climate. The findings with topical antibiotic usage may not be applicable in tropical and subtropical climates114. The wounds in this study were not examined routinely by medical or nursing staff at 6-9 months after surgery, and long term outcomes were limited to the patient’s perception at self - assessment. Ideally, both patient and professional long term wound assessments would have been undertaken. Wound infection was assessed clinically rather than by the culture of wound swabs. The trial setting was that of a community dermatological surgery centre where wound swabs would not taken routinely where infection was a concern.

The incidence of wound infection was lower than expected when the study, including its power, was designed. With the identification of a placebo infection incidence lower than expected, the power to find benefit from ointment is reduced. However, the low incidence of infection in the no ointment group further raises the question as to why infection prophylaxis need be attempted in skin excision surgery.

Of concern was the finding that the rate of skin edge necrosis was higher in the mupirocin group. Although the incidence was only 1.1 per cent in this group, it included six of the seven cases of postoperative skin necrosis found in the study, raising the possibility that mupirocin may impede skin edge perfusion.

Individual patient considerations that influence the decision to use prophylactic antibiotics for skin surgery include risk of endocarditis, recent joint replacement surgery and wound contamination.

In keeping with other investigators,79, 114 the present study  found that surgical wounds on the leg  had a significantly increased  risk of infection. However, even these sites at greater risk of infection did not benefit from the application of an antibiotic ointment before wound closure.

Conclusion

This prospective randomized controlled trial showed that a single application of paraffin or mupirocin ointment applied at the time of wound dressing made no difference to infection rates, pain experienced, wound discomfort, or long term wound aesthetic outcomes when compared with no ointment application. Mupirocin use was associated with a higher incidence of skin necrosis. These findings argue strongly against the use of ointment on a clean surgical wound before the application of a moist occlusive dressing. Considering issues of antibiotic resistance, topical mupirocin should no longer be applied to clean surgical wounds.

 

Table 1: Characteristics of and number of wounds per enrolled patients

 

No ointment

Paraffin

Mupirocin

Total

p-++

No.of patients

247

269

262

778

 

Mean (s.d.) Age (years)

58.3 ± 17.3

60.5 ± 18.0

59.1 ± 18.3

59.3 ± 18.3

 0.420

No. of men*

140 (56.7)

138 (51.3)

140 (53.4)

418 (53.7)

 0.470

No. of Wounds included in study

510

729

562

1801

 0.273

Median no. of wounds per pt#

1 (2)

1 (3)

1 (2)

1 ( 1)

 0.110

Values in parentheses are * percentages and # interquartile range unless indicated otherwise.

 

Table 2: The incidence of post-operative complications per wound managed

 

No ointment

(n=510)

Paraffin (n=729)

Mupirocin (n=562)

Total (n=1801)

P*

Wound infection

7 (1.4)

12 (1.6)

13 (2.3)

32 (1.8)

0.490

Suture abscess

1

5

5

11

 

Cellulitis

5

5

7

17

 

Infective necrosis

0

2

0

2

 

Purulent sutured wound

1

0

1

2

 

Lower limb (n=225)@

1 of 57 (1.8)

5 of 102(4.9)

4 of 66(6.1)

10 of 225 (4.4)

0.490 #

Scar complictns (other)

0 (0)

5 (0.7)

7 (1.2)

12 (0.7)

0.044

Skin necrosis

0

1

6 #

7

 

Hypertrophic scar

0

2

1

3

 

Wound elevation

0

1

0

1

 

Wound depression

0

1

0

1

 

Post operative bleed

6 (1.2)

4 (0.5)

2 (0.4)

12 (0.7)

0.230

Wound dehiscence

3 (0.6)

6 (0.8)

4 (0.7)

13 (0.7)

0.890

Other complications

2 (0.4)

7 (1.0)

1 (0.2)

10 (0.6)

0.510

Total complications

18 (3.5)

34 (4.7)

27 (4.8)

79 (4.4)

0.590

Values in parentheses are percentages. * Pearson’s x2 test. # P=0.007 versus no ointment and paraffin. @ Excisions on the lower limbs.

 

Table 3: Patient reporting (for the first wound treated) of post-operative pain, dressing inconvenience and final appearance of surgical scar.

 

No ointment (n=180)

Paraffin (n=202)

Mupirocin (n=194)

Total (n=576)

Wound pain

 

 

 

 

No pain

58 (32.3)

63 (31.2)

66 (34.0)

187 (32.5)

Minimal – no analgesia required

72 (40.0)

76 (37.68)

73 (37.6)

221 (38.4)

Mild – paracetamol sufficient

40 (22.2)

53 (26.2)

42 (31.6)

135 (23.4)

Moderate – stronger analgesia required

4 (2.2)

5 (2.5)

7 (3.6)

16 (2.8)

Severe – not relieved by analgesia

2 (1.1)

2 (1.0)

0 (0)

4 (0.7)

Worst pain ever experienced

0 (0)

0 (0)

0 (0)

0 (0)

Did not answer

4 (2.2)

3 (1.5)

6 (3.1)

13 (2.3)

Dressing problem *

 

 

 

 

No inconvenience from dressing

99 (55.0)

96 (47.5)

87 (44.8)

282 (49.0)

Nuisance – but no interference

74 (41.1)

94 (46.5)

91 (46.9)

259 (45.0)

Disruptive or embarrassing

2 (1.1)

2 (1.0)

3 (1.5)

7 (1.2)

Could not tolerate dressing

0 (0)

3 (1.5)

2 (1.0)

5 (0.9)

Did not answer

5 (2.7)

6 (3.0)

10 (5.2)

21 (3.6)

 Appearance of surgical scar at 6-9 months

 

 

 

 

Excellent or very good

130 (72.2)

151 (74.85)

146 (75.3)

427 (74.1)

Good

25 (13.9)

24 (11.92)

23 (11.9)

72 (12.5)

Fair

10 (5.6)

16 (7.9)

14 (7.2)

40 (6.9)

Poor / very poor

9 (5.0)

4 (2.0)

1 (0.5)

14 (2.4)

Did not answer

6 (3.3)

7 (3.5)

10 (5.2)

23 (4.0)

 

 

 

 

 

Values in parentheses are percentages. There were no significant differences between the groups. * One patient from the paraffin group and one from the mupirocin group commented on the dressing, but did not select a category.