Sildenafil in the treatment of pressure ulcer: a randomised clinical trial

Abstract

Pressure ulcer (PrU)‐related hospitalisation and mortality are critical issues in medical and surgical patients. Although animal studies have suggested the beneficial effects of sildenafil on wound healing, related clinical data are lacking. This is the first clinical study that has evaluated the effects of topical sildenafil on PrU healing in human subjects. Enrolled patients were randomly allocated to receive topical sildenafil (10%) ointment or placebo daily. Wound healing was assessed visually and photographically by the change in wound score according to two‐digit Stirling scale. Decreases in grades of the PrUs were significantly higher in sildenafil group compared with placebo group (P < 0·001). In addition, surface areas of ulcers in sildenafil group were significantly reduced compared to the control group at day 14 of intervention (P = 0·007). It appears that these effects may be mediated by improvement of microvascular reperfusion in the skin and soft tissue. Further study to emphasise the role of topical sildenafil in the prevention or treatment of PrUs in hospitalised patients is required.

Introduction

Patients admitted to intensive care unit (ICU) are vulnerable to develop pressure ulcers (PrUs) because of several reasons including immobility and administration of several therapeutic agents that blunt appropriate reactions to increased tissue pressure ¹. Also, haemodynamic abnormalities, surgery, positive pressure ventilation, heart failure, anaesthesia and other conditions cause decreased local perfusion and adversely affect pressure sore healing in these patients ².

PrU‐related hospitalisation and mortality have been increased during the last 10 years ^{3, 4}. Infectious complications of PrU account for more than 60 000 deaths annually ⁵. In addition, the cost of PrUs care is increasing. In this regard, economic burden of PrU has been estimated to range from $500 to $40 000 per ulcer depending on its stage in the USA ⁶. Studies have also implicated that early diagnosis and management of PrU have positive effects on physical, emotional and financial issues of PrU treatment ^{6, 7}.

One of the critical events in wound healing is remodelling and angiogenesis, which is crucial for restoration of blood flow and oxygen supply to the injured tissue ⁸. Nitric oxide (NO) has beneficial effects on angiogenesis, endothelial cell proliferation, remodelling and enhancing oxygen delivery during wound healing ^{9, 10, 11, 12}. However, wound healing related to NO was also attributed to potentiating the clotting process ¹³, regulation of vasodilation ¹⁴, scavenging oxidative stress component ¹⁵ and even antimicrobial activity ¹⁶. Therefore, NO‐releasing agents including topical NO donor ¹⁷ or the precursor of NO such as l‐arginine are promising therapy for wound healing in diabetic mice ¹⁸. Reverse of vasoconstriction due to topical NO‐releasing formulations has been demonstrated to be helpful in localised systemic sclerosis and Raynaud's disease ^{19, 20}. On the other hand, decreased NO in wound site has been related to delay in wound healing in animal models ^{21, 22, 23, 24}. Antiplatelet effect of sildenafil with enhancing NO actions and improved microcirculation showed beneficial effects on wound healing in experimental models ²⁵. It was effective in conditions with diminished skin blood flow and poor vascularisation especially in Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis ^{26, 27, 28, 29}.

Although animal studies suggested the beneficial effects of sildenafil on wound healing related clinical data are lacking ³⁰. Consequently, this is the first clinical study that was conducted to evaluate the effects of topical sildenafil on PrU healing in human subjects.

Method

This randomised, controlled trial (IRCT ID: IRCT201105303449N6) was conducted over a period of 2 years (from August 2010 to November 2012) in the general ICU of Imam Khomeini Hospital, affiliated to Tehran University of Medical Sciences, Tehran, Iran. This study was approved by Institutional Review Board and the Medical Ethics Committee of the hospital.

Selection of patients and treatment

Patients with grades I and II PrUs according to two‐digit Stirling scale were eligible to enter the study. Those with grade III or IV PrU, acute infection of ulcer with typical findings of warmth, purulent drainage and advancing erythema ³¹, hypersensitivity reaction to topical formulation or unwilling to participate in the study were excluded. Change in wound exudates, increased pain and friability, bright red granulation tissue, breakdown of wound surface or new areas of skin breakdown and foul odour of wound were considered as signs of infection ^{32, 33, 34}.

Totally, 168 patients were screened and 122 of them had inclusion criteria of the study. These patients were categorised in the study (sildenafil) or control (placebo) group based on the simple randomisation method. Sixty patients in the sildenafil and 62 patients in the placebo group were enrolled into the randomisation (Figure 1). The study group received topical sildenafil ointment daily and the control group received daily topical application of placebo ointment. All patients received standard care for PrU including reduction of local pressure on damaged skin, maintaining the clean base of ulcer and correcting patients' nutritional conditions and other medical factors such as blood sugar level that might interfere with the healing process ².

Figure 1.

Consort flowchart of the study. ¹Loss of follow‐up (six patients): one patient died, two patients discharged from intensive care unit (ICU) and wound exacerbation occurred in three patients. ²Loss of follow‐up (four patients): one patient died, two patients discharged from ICU and wound exacerbation occurred in one patient. ³Loss of follow‐up (two patients): one patient discharged from ICU and one patient died. ⁴Loss of follow‐up (four patients): one patient died, one patient discharged from ICU and wound exacerbation occurred in three patients.

Preparation of topical formulation

Vaseline, beeswax and span 60 were used to formulate sildenafil ointment base. For preparation of sildenafil 10% ointment, sildenafil powder was levigated with oleic acid to form a smooth paste and then mixed with ointment base to form the final ointment. Placebo ointment was also prepared, which was consisted of only base formulation without sildenafil.

Modified Draize test was used to evaluate the biocompatibility of sildenafil 10% through assessing skin irritation on intact skin of rabbits. In all animals treated with the sildenafil 10% ointment, no oedema or erythema was observed, whereas the positive control group treated with the 0·1% histamine showed oedema and erythema. On the basis of this test, it was found that sildenafil 10% ointment did not cause significant irritant effects on the skin.

Mouse ear swelling test was also conducted to assay the skin sensitisation of sildenafil. Ear thickness of the test and control ears was measured with a micrometer 24 and 48 hours after the application of sildenafil 10%. The difference of ear swelling between test and control was not significant and this formulation did not show any sensitising effect on the skin.

Wound evaluation

Ulcers of the admitted patients were evaluated for inclusion and exclusion criteria during the study. They were evaluated daily by exact wound inspection for 2 weeks. Wound healing was assessed visually and photographically by the change in wound scores according to two‐digit Stirling scale ³⁵. In addition, changes in wound surface area were assessed during ulcer evaluation. If a patient had more than one PrU, the ulcer with the highest score was assessed in the study.

Outcomes and data collection

Patients' demographic and general medical information including sex, age, medical diagnosis (surgical, medical or trauma), Acute Physiology and Chronic Health Evaluation (APACHE) II score, past medical history, laboratory data, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP) and wound location were recorded.

Patients' nutritional status was assessed based on the serum albumin level and duration of enteral or parenteral support. Medications that may alter wound healing (such as oral atorvastatin, sildenafil, heparin, insulin and supplements including vitamins and trace elements) were also recorded ^{30, 36, 37}. Moreover, factors affecting tissue perfusion and oxygenation including haemodynamic instability and baseline diseases were also considered. We defined haemodynamic instability as a clinical condition of perfusion failure represented by shock, hypotension, abnormal heart rates, cold extremities, peripheral cyanosis or mottling together with decreased urine output during more than 50% of hospital stay.

Data analysis

Continuous and categorical variables were expressed as mean ± standard deviation (SD) and percentages, respectively. Categorical variables were compared using χ ² test. Fisher's exact test was used when expected cell counts of less than 5 comprise 25% or more of a table. One‐sample Kolmogorov–Smirnov test was used to evaluate normal distribution of continuous data. Because the data were non‐parametric, the Mann–Whitney non‐parametric tests were performed to compare quantitative data. Analysis of covariance (ANCOVA) was used with gender as a covariate to remove the influence of gender between groups.

The changes in the stage of PrUs during study were analysed by using repeated‐measures analysis of variance. The level of statistical significance for all statistical analyses was set at P < 0·05. Data analysis was done with SPSS 11.5 for Windows.

Results

Among the included patients, 52 patients (28 males and 24 females) in the sildenafil group and 53 patients (41 males and 12 females) in the control group completed the study. Eight patients in the sildenafil group (three patients with exacerbation of wounds which required further intervention and debridement; three patients who transferred to medical wards; and deaths of two patients) and nine patients in the placebo group (four patients with exacerbation of wounds which required further intervention and debridement; three patients who transferred to medical wards; and deaths of four patients) were excluded from the study (Figure 1). There was no significant difference in the number of excluded subjects between the two groups (P = 0·12).

Patients in both groups did not differ significantly in the cause of ICU admission, haemodynamic instability, APACHE II scores, ESR and CRP, and were comparable with regard to their past medical history and medications that may interfere with wound healing. Also, serum albumin and duration of nutritional support were comparable between the groups. The patients' ulcers located primarily on the sacrum followed by the buttock and heel. Basic demographic, laboratory and clinical characteristics of the patients are summarised in Table 1.

Table 1.

Characteristics of the patients

Variables		Groups
		Placebo	Sildenafil	P‐value
Age, mean (SD), years		62·30 (18·60)	62·00 (20·20)	0·97
Sex	Male, n (%)	41 (77·4%)	28 (53·8%)	<0·001
	Female, n (%)	12 (22·6%)	24 (46·2%)
Creatinine, mean (SD) (mg/dl)		1·2 (0·7)	0·9 (0·4)	0·08
Erythrocyte sedimentation rate (mm/hour)		46·5 (32·1)	47·5 (42·5)	0·52
C‐reactive protein (mg/l)		49·8 (22·9)	51·8 (53·5)	0·75
APACHE II score, mean (SD)		21·6 (4·3)	20·2 (6·5)	0·67
Haemodynamic instability during hospitalisation course		43·2%	27·0%	0·13
Past medical history
Cardiovascular disease		29·2%	18·4%	0·25
Diabetes mellitus		21·9%	11·3%	0·07
Pulmonary diseases		20·8%	23·7%	0·75
Malignancy		19·8%	15·5%	0·47
Other medical conditions		16·7%	31·6%	0·10
Diagnostic category
Medical		79·2%	59·5%	0·05
Trauma		14·6%	16·2%
Surgery		6·3%	24·3%
Wound location
Sacrum		24·5%	26·4%	0·71
Heel		11·3%	15·1%
Buttock		9·4%	13·2%
Other sites		54·8%	45·3%
Albumin, mean (SD) (mg/dl)		3·1 (0·4)	2·9 (0·6)	0·10
Duration of nutritional support, mean (SD), days		6·2 (1·9)	7·0 (6·5)	0·42

SD, standard deviation.

To evaluate wound healing, grade and surface area of PrUs were compared at days 7 and 14 after intervention (Table 2). Although the grade of PrU was significantly lower in the sildenafil group at baseline, the decrease in grade of PrUs was significantly higher in this group compared with placebo group at days 7 and 14. In addition, after applying ANCOVA to control for differences in gender between the two groups, differences in scores of PrUs remained the same.

Table 2.

Comparison of ulcer scores and surface area between the groups

Variable	Day*	Groups		P‐value
		Placebo	Sildenafil
Pressure ulcer score†, mean (SD)	0	1·74 (0·65)	1·5 (0·61)	0·001
	7	1·74 (0·75)	1·1 (0·72)	<0·001
	14	1·71 (0·78)	0·9 (0·60)	<0·001
Changes in surface area of the ulcers†
Increase	7	26·4%	13·5%	0·242
Decrease		3·8%	5·8%
No change		69·8%	80·8%
Increase	14	32·1%	9·6%	0·007
Decrease		5·7%	17·3%
No change		62·2%	73·1%

^*Days after intervention.

^†Score according to the two‐digit Stirling scale.

In addition, surface areas of ulcers in the sildenafil group were significantly reduced compared to the control group following 14 days of intervention. However, these changes were not significantly different between these groups on day 7. Similar results were observed when gender was considered as covariate in ANCOVA.

Discussion

To the best of our knowledge, this is the first randomised, placebo‐controlled clinical trial that has evaluated the effects of topical sildenafil in PrU treatment. Wound healing was more significant in patients treated with topical sildenafil than placebo and this formulation appears to be a useful adjunct in the treatment of PrUs. No hypersensitivity or local skin reaction due to sildenafil 10% was detected during the study period.

During the years 2000–2010, several animal studies and some case reports described the role of sildenafil on wound healing due to ischaemia. Also, different case reports and small clinical studies reported the beneficial effects of sildenafil on ulcers related to systemic sclerosis ³⁰. These studies highly suggest that sildenafil may be valuable candidate for tissue repair and wound healing. However, apart from this study, no other study has considered sildenafil for treating PrUs until now.

Sildenafil might exert its beneficial actions on the process of wound healing through different mechanisms including vasodilation and increasing perfusion ³⁸, improved microcirculatory haemodynamics through inhibition of platelet aggregation and reducing thrombosis ³⁹, stimulating angiogenesis ⁴⁰, reducing inflammatory responses and inducing apoptosis of adhesion fibroblasts ⁴¹.

Targeted sildenafil delivery to the skin is possible by topical administration of sildenafil. Using a topical form of sildenafil can prolong its exposure to the skin and overcome frequent use of systemic sildenafil because of its short half‐life ⁴². Topical formulation of sildenafil was previously applied for chronic anal fissure and showed beneficial effects ^{43, 44}. Among topical formulations, oil‐based skin products tend to stay longer on the skin. The oil base of the formulation makes it waterproof; therefore, it will not be removed from skin surfaces following sweating or diarrhoea. Moreover, it will stay on the skin in spite of rubbing the body area against other areas. Accordingly, oil‐based ointment is superior to other topical formulations in delivering adequate dose of topical medications.

Several types of topical formulations have been recommended for PrU prophylaxis or treatment. Topical formulations of zinc sulphate ⁴⁵, aluminium hydroxide ⁴⁶, oxyquinoline ⁴⁷, cadexomer ⁴⁸, phenytoin solution ⁴⁹, ointment of live yeast cell derivative ⁵⁰, cream of barley extract ⁵¹, vitamin A ointment ⁴⁶, topical insulin ⁵² and dialysate ⁵³ have been demonstrated to accelerate the wound healing process. In addition, wound environment modulators such as protease‐modulating matrix ⁵⁴ and acute wound factors such as recombinant platelet‐derived growth factor ^{55, 56}, nerve growth factor ⁵⁷, transforming growth factor beta ⁵⁸, granulocyte‐macrophage colony‐stimulating factor ⁵⁹ and fibroblast growth factor ⁶⁰ accelerate the healing process of pressure wounds and offer great promise. However, the value of growth factors in clinical practice needs to be confirmed by considering their high cost. Semelil, the topical herbal extract, also shortened the time of PrU healing in human subjects ⁶¹. Although antiseptics are inexpensive, their role in maintenance therapy of non‐healable wounds or prevention of ulcer deterioration was not confirmed in randomised clinical trials ^{37, 62}.

Many factors such as haemodynamic abnormalities, nutritional status, heart failure, surgery, anaesthesia and positive pressure ventilation may contribute in healing of PrU ^{40, 63, 64}. In our patients, mean scores of the APACHE II, haemodynamic instability, nutritional status and causes of ICU admission that may affect wound healing were not significantly different between the groups.

Another confounding factor for tissue repair is excessive inflammation, which can delay the repairing phase during wound healing process ^{65, 66}. Therefore, ESR and CRP were assessed as the inflammatory markers, and they were not significantly different between the two groups.

Until now, no superiority of topical interventions had been reported in the published trials of PrU treatment ³⁷. There is insufficient evidence to suggest the best topical therapy for PrUs. Clinicians should select the optimal modality by considering the grade of ulcer, cost of intervention, clinical setting, patient comfort and ease of use. In addition to effectiveness, sildenafil ointment appears to be cheaper than many other medical modalities applied for PrUs. Several scales were introduced to assess severity of PrU, but the best scale for assessing severity of PrUs has not been introduced ^{67, 68, 69, 70, 71}. Regarding its usefulness for evaluating low‐grade ulcers, we selected two‐digit Stirling scale for assessing PrU status in the included patients ^{67, 68, 69}.

Some limitations exist for our study. Small sample size was the main limitation of this study. We have assessed patients' nutritional status only based on the serum albumin and duration of metabolic support. More appropriate tools such as anthropometric parameters and precise serum nutritional biomarkers must be considered for future studies.

Conclusion

Significant improvement in PrU of patients who had received topical sildenafil 10% for 2 weeks compared with placebo was noted in this study. It appears that this effect may be mediated by improvement of microvascular reperfusion in the skin and soft tissue. Further large, multicentre studies are required to emphasise the beneficial role of topical sildenafil in the prevention or treatment of PrU in hospitalised patients in different settings.