Polyurethane foam dressings ameliorating local adverse effects of azacitidine: a randomized controlled trial

Abstract

This study investigated the use of polyurethane foam dressings to prevent local adverse reactions of subcutaneous azacitidine injection. Patients receiving a subcutaneous azacitidine injection were randomly divided into experimental and control groups. A total of 55 patients were included in each group. A polyurethane foam dressing was used to cover the injection site of patients in the experimental group. Conventional treatment was used in the control group. Injection site pain and local skin reactions were assessed after the intervention in both groups. The score and duration of pain, the incidence and duration of local skin adverse reactions, and the incidence of severe reactions in the experimental group were significantly lower than in the control group (p < 0.05). Polyurethane foam dressing can effectively reduce local adverse reactions of subcutaneous injection of azacitidine, relieve pain, shorten the duration of local pain and adverse reactions, and improve the quality of nursing.

Keywords:

• Polyurethane foam dressing
• azacitidine
• subcutaneous injection
• local reaction
• subcutaneous induration

Introduction

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are myeloid tumors originating from hematopoietic stem cells [1,2]. The survival period of patients with MDS or AML is short when they cannot tolerate intensive treatment or stem cell transplantation. This has led to the emergence of demethylating agents (hypomethylating agents, HMAs), which are effective for such patients [3]. Due to the relatively high efficacy and acceptable safety of the demethylating drug azacitidine, the United States’ Food and Drug Administration approved its marketing in May 2004 for the treatment of MDS and AML [4]. In China, HMAs are first-line treatments for patients with high-risk MDS who cannot receive hematopoietic stem cell transplantation and patients with AML who are intolerant to intensive chemotherapy. The route of administration of azacitidine is subcutaneous. Although subcutaneous administration is less invasive than intravenous administration, the risk of injection site reactions is higher [5]. Subcutaneous injection of azacitidine can cause erythema, ecchymosis, skin nodules, hemorrhage, swelling and induration, pain, and even bullous ecchymosis, causing discomfort to the patient [6,7]. A polyurethane foam dressing is a type of wound dressing constructed mainly of polyurethane foam with a porous structure which can be used with or without a backing. The polyurethane foam dressing consists of a reactive polyurethane film layer and self-adhesive polyurethane matrix layer (containing a highly absorbent substance), which is waterproof, bacteria-resistant, and breathable. The material is soft and sticky; therefore, the operator can cut it according to the injection site, and it can be pasted repeatedly, making it convenient, economical, and practical. It has good wound exudate absorption capacity; it can simultaneously provide a protective wound barrier and maintain a wet environment for wound healing [8]. Polyurethane foam dressings are widely used to improve healing in the treatment of pressure ulcers, donor wounds, and skin ulcers [9,10]. This study investigates the use of polyurethane foam dressings in the prevention of local adverse reactions caused by azacitidine when administered subcutaneously using a ‘Z’ shape injection.

Materials and methods

Design and participants

Using a prospective, randomized, and controlled method, patients treated with azacitidine in the Department of Hematology, Union Hospital Affiliated to Fujian Medical University from April 2021 to June 2021 were selected as the research subjects. The inclusion criteria were: (1) age ≥18 years, (2) diagnosis of MDS and AML in line with the 2016 revision of the World Health Organization diagnostic criteria for MDS and AML [11], and (3) provision of consent to participate by the patients and their families. The exclusion criteria were: (1) allergy to azacitidine; (2) patients with skin ulceration or pustulosis, psoriasis, urticaria, macular or papular lesions, and other skin diseases; (3) patients with diabetes receiving subcutaneous treatment; (4) abnormal mental condition; and (5) allergy to polyurethane foam dressing. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Fujian Medical University Union Hospital (2021KY046).

Blinding procedure

A prospective, randomized, and controlled study design was adopted, with a ratio of 1:1 between the experimental group and the control group. Due to the particular nature of polyurethane foam dressings, this study could not be performed in a fully double-blinded manner. In terms of efficacy evaluation records and treatment practitioners, the two groups were separated. Outcome evaluators and statistical analysts were blinded. Blinding was maintained by the custodian of the random sequence, who did not participate in the process of subject recruitment, intervention, outcome index evaluation, or data analysis. The first blind codes were ‘A’ and ‘B’ to represent the outcome of the assignment of participants (treatment group or control group), and the second blind codes represented the true meaning of ‘A’ and ‘B.’ The blinding code was uncovered twice in the course of the study. The first time, after the database was turned off, the random sequence keeper handed the participants’ codes ‘A’ and ‘B’ to the statistician. The second time, after all data analysis was completed, the random sequence keeper announced the true meaning of ‘A’ and ‘B.’

Injection and post-injection methods

The patients were divided into an experimental group and a control group using the random number table method. Each group was composed of 55 patients. Each patient was administered azacitidine (75 mg/m²) subcutaneously using the ‘Z’ injection method and indwelling bubble technique once daily for 7 days. This injection method has been previously published [12]. Venetoclax was not used. After extracting the azacitidine suspension, the nipple of the syringe was vented and replaced with a 1 mL syringe needle (0.45 × 16 mm). Before the injection, the operator placed their left hand on the skin and gently staggered the subcutaneous layer and intramuscular tissue by approximately 1 cm, inserted the needle 1 cm in front of the finger at 90°, submerged the needle 1/2–2/3 (approximately 8–10 mm), and withdrew the plunger of the syringe. If there was no bleeding, pushed the liquid injection, including the reserved air. The finger was released after the injection was completed, and then the needle was pulled out. The skin layer moved back to its original position. The operator selected a site with relatively thick subcutaneous fat for the injection (the upper arm and abdomen are recommended). Each injection was be done in a different position, and the new injection point was at least 2.5 cm away from the last injection point to avoid tenderness, congestion, redness, or lumps. After the injection, 0.9% normal saline was used to clean the injection site and surrounding skin of the patients in the experimental group, and a 5 × 5 cm polyurethane foam dressing (Allevyn Thin, 4 in. × 4 in., Smith & Nephew) was used on all the injection sites to cover the puncture point for 7 days and mark its location. The injection site was evaluated when the dressing was removed every 24 h after the injection. If the effect of the polyurethane foam dressing is affected by dampness or shedding, change the dressing immediately. Conventional treatment was used in the control group after the injection of azacitidine, including explanation of the purpose of subcutaneous injection, the appropriate posture, and the avoidance of hot or cold compresses after injection. Outcome evaluators stripped the dressing every 24 h to assess pain at the injection site and the occurrence of adverse reactions in both groups.

Observation indexes

Pain assessment

The degree of local skin pain was rated using a pain score, which ranged from 0 to 10. Zero signified painless, and 10 represented maximum pain. The highest score recorded within 7 days was considered.

Evaluation of local skin reactions

The patients’ skin was evaluated for redness, swelling, pain, sclerosis, rash, and other reactions at the injection site. The observed local reactions were divided into mild (redness, swelling, induration, and rash diameter < 15 mm in diameter), moderate (redness, swelling, induration, rash 15–30 mm in diameter), and severe (redness, swelling, induration, rash > 30 mm in diameter, or ecchymosis with bulla).

Calculation of sample size

This study was a randomized controlled trial, in which the experimental group was the polyurethane foam dressing group, and the control group was the blank control group. Local adverse reactions of the subjects were the primary outcome indexes observed, while the local pain were the secondary outcome indexes. The sample size was estimated based on the incidence of major outcome indicators. According to a preliminary experiment, the incidence of local adverse reactions in the control group was 80%, and the incidence of local adverse reactions in the experimental group was expected to be 53%. The sample size was estimated according to the difference test formula for comparison of means between two randomized independent groups. The type I error (α) was set as 0.05 and the test efficiency (1 − β) was set as 0.9, with M1 = 0.2, M2 = 0.53, and N1:N2 = 1. The sample size was calculated by the formula N1 = N2 = 50. Considering a 10% sample dropout rate, N1 = N2 = 55, thus yielding a total of 110 cases. $$n=\frac{{2\overline{p}\overline{q}\left(Z_{\alpha }+Z_{\beta }\right)}^2}{{\left(p1-p2\right)}^2}$$

Statistical analysis

All data were analyzed using SPSS version 25.0 statistical software. Normally distributed measurement data were expressed as mean ± standard deviation; the t-test was used for comparison between groups. Non-normally distributed data were expressed as median and quaternary intervals (M[P25, P75]); the rank sum test was used for comparison between groups. Enumerative data were expressed as absolute number and percentage; the chi-square test was used for comparison between groups, and the Kruskal–Wallis H test was used for comparison between grade data. Statistical significance was set at a = 0.05 and p < 0.05.

Results

From 1 March 2020 to 30 June 2020, 123 subjects were included in this study. Thirteen patients who were receiving subcutaneous treatment of diabetes were excluded. Finally, 110 patients were included in the analysis: 43 with MDS and 67 with AML. The age range of the patients was 18–77 (52 ± 17.8) years.

Comparison of the characteristics of the two groups

Table 1 shows the clinical characteristics of the two groups. There were no statistically significant differences in age, sex, disease type, or other variables between the two groups.

Table 1. Comparison of baseline data between the experimental group and the control group.

Variable	Experimental group (N = 55)	Control group (N = 55)	t/z/X^2	p value
Sex			0.34^a	0.55
Male	32	35
Female	23	20
Age	51 ± 14.9	53 ± 18.3	0.63^b	0.53
BMI	22.6 ± 2.7	22.9 ± 2.6	−0.56^b	0.55
Disease type			0.04^a	0.85
AML	33	34
MDS	22	21

^aX² value; ^bT value. AML: acute myeloid leukemia; BMI: body mass index; MDS: myelodysplastic syndrome.

Comparison of pain between the two groups

The highest pain score (4.5 ± 2.0 vs. 2.1 ± 1.2), lowest pain score (1.6 ± 1.1 vs. 3.1 ± 1.4), and duration of pain (d) (2.3 ± 1.1 vs. 4.6 ± 1.9) in the experimental group were lower than in the control group within 7 days after subcutaneous azacitidine injection, and the differences were statistically significant (p < 0.05). However, there was no significant difference in the occurrence time of peak pain between the experimental group and the control group (p > 0.05), as shown in Table 2.

Table 2. Comparison of pain at the subcutaneous injection site of azacitidine between the experimental group and control group (N).

Variable	Experimental group (N = 55)	Control group (N = 55)	Test statistic	p value
Peak pain score	2.1 ± 1.2	4.5 ± 2.0	7.631^a	<0.001
Low pain score	1.6 ± 1.1	3.1 ± 1.4	−6.248^a	<0.001
Duration of pain (d)	2.3 ± 1.1	4.6 ± 1.9	−7.769^a	<0.001
Time of peak pain			−^b	0.800
First day	15	12
Second day	23	28
Third day	10	8
Fourth day	3	5
Fifth day	3	2
Sixth day	1	0
Seventh day	0	0

^aIs a t-test, and the test statistic is T; ^bis a chi-square test, and the test statistics are continuously corrected chi-square values.

Comparison of local adverse reactions at the injection site between the two groups

The total incidence of local adverse reactions at the subcutaneous injection site of azacitidine was 65.5% (Table 3). The incidence of local adverse reactions at the subcutaneous injection site of azacitidine in the experimental group was 45.5%, significantly lower than the 85.5% in the control group (p < 0.05). Regarding the severity of local adverse reactions in the experimental group, the incidence of moderate (7.3% vs. 34.5%) and severe adverse reactions (3.6% vs. 21.8%) was lower in the experimental group than in the control group. The occurrence of the maximum local adverse reaction was mainly on the second day in the experimental group (15/25, 60.0%) and on the third day in the control group (25/47, 53.2%), and the difference was statistically significant (p < 0.05). In terms of the duration of local adverse reactions, the duration in the experimental group was significantly shorter than in the control group (2.9 ± 1.5 vs. 5.2 ± 1.6), and the difference was statistically significant (p < 0.05), as shown in Table 3. There were no cases of bullous ecchymosis in the experimental group, whereas three patients had bullous ecchymosis in the control group; treatment was interrupted in one of them.

Table 3. Comparison of local adverse reactions at the injection site between the experimental group and control group.

Variable	Experimental group (N = 55)	Control group (N = 55)	Test statistic	p value
Degree of local adverse reactions			27.080^a	<0.001
None	30 (54.4)	8 (14.5)
Mild	19 (34.5)	19 (34.5)
Moderate	4 (7.3)	16 (29.1)
Severe	2 (3.6)	12 (21.8)
Time of the most serious local adverse reaction			−^b	0.013
First day	2	3
Second day	15	12
Third day	4	25
Fourth day	3	5
Fifth day	1	2
Sixth day	0	0
Seventh day	0	0
Duration of local adverse reaction (d)	2.9 ± 1.5	5.2 ± 1.6	−7.777^c	<0.001

^aIs a chi-square test, and the test statistic is χ²; ^bis a chi-square test, and the test statistics are continuously corrected chi-square values; ^cis a t-test, and the test statistic is T.

Discussion

This study showed that the total incidence of local adverse reactions at the subcutaneous injection site of azacitidine was 65.5%. Platzbecker et al. [13] found that 60% of patients injected with azacitidine had local skin reactions, which was consistent with the results of this study. Azacitidine is an analog of pyrimidine nucleoside cytidine, which acts on RNA to interfere with mRNA and protein metabolism. It can be converted to decitabine triphosphate, which inhibits deoxyribonucleic acid (DNA) methyltransferase inhibitors, thereby affecting cell differentiation, gene expression, and DNA synthesis and metabolism. This contributes to cytotoxic effects [14].

Subcutaneous induration is an adverse reaction of the subcutaneous injection of azacitidine, which is considered to be a local inflammatory reaction. Subcutaneous induration is composed of abnormally enlarged fat cells and fibrous tissue hyperplasia, which involves the adjacent reticular dermis and subcutaneous vascular tissue; this affects local metabolism and causes poor local blood circulation in the skin. These result in slow local absorption of drugs, prolonged residence time in subcutaneous tissue, and formation of subcutaneous sclerosis. The main influencing factors for the formation of subcutaneous sclerosis include:

Drug factors

Azacitidine is a demethylated drug with cytotoxic effects, which can cause extensive damage to the skin at the injection site. Plume et al. [15] conducted a local skin biopsy study on azacitidine, which showed lymphoid infiltration around the blood vessels at the injection site.

Patient factors

Patients with MDS/AML are immunosuppressed, have poor constitution, reduced activity, poor blood circulation, and are malnourished; these affect the rate of drug absorption.

Operational factors

When the drug is injected several times at the same site, the muscle fibers undergo atrophy and degeneration, reducing the absorption capacity of the drug and increasing the time of availability of the drug at the site, resulting in sclerosis.

Injection site

The common sites for subcutaneous injection are the lower edge of the upper arm deltoid muscle, abdomen, and outer thigh. The ‘Z’ injection method was used in this study to close the injection tunnel. The injection content was divided severally into volumes below 3 mL; this effectively prevents the drug from penetrating the skin surface. By using the indwelling bubble technique, the liquid can enter the subcutaneous tissue and control the dead cavity. Administering the injection on the lower edge of the upper deltoid muscle and abdomen and other sites that facilitate absorption reduces local skin sclerosis caused by subcutaneous injection of azacitidine.

Subcutaneous injection of azacitidine can damage the skin directly and even cause necrosis. Although most of these local reactions (e.g. subcutaneous sclerosis and local erythema) are self-limited, they may cause discomfort such as irritation and pain and even lead to serious skin problems such as bullae and ecchymosis, which may limit the choice of injection site and lead to treatment interruption in severe cases [7]. Therefore, skin problems caused by subcutaneous injection of azacitidine should not be ignored. Santini et al. [16] suggested that to reduce the occurrence of local adverse reactions, friction should be avoided, ice should be applied within 4 h, and the air sandwich technique should be used. Platzbecker et al. [13] suggested that topical evening primrose oil can reduce skin reactions at the injection site. Almeida et al. [17] reported that local use of low-dose steroids is effective for rashes caused by azacitidine. Ferruccio et al. [18] changed the maximum injection volume from 2 mL to 3 mL, thereby reducing the injection site reaction rate of azacitidine. However, none of these methods significantly affected the outcome.

In this study, the application of the polyurethane foam dressing resulted in the peak pain score, lowest pain score, and duration of pain being lower in the experimental group than in the control group. In addition, the incidence of local adverse reactions in the subcutaneous injection site of azacitidine in the experimental group was 45.5%, which was significantly lower than that in the control group (85.5%). Moreover, the incidence of moderate and severe adverse reactions and the duration of adverse reactions in the experimental group were significantly lower than in the control group. Therefore, the polyurethane foam dressing effectively reduces pain, the incidence of subcutaneous induration caused by azacitidine, the severity of local skin reactions, and the duration of local pain and adverse reactions caused by azacitidine. Polyurethane foam dressings are mostly used to treat and prevent mechanical phlebitis and drug-induced phlebitis. A randomized controlled study of pressure ulcers in 359 elderly patients with hip fractures by Forni et al. [19] found that polyurethane foam dressings reduced the incidence of pressure ulcers from 15.4% to 4.5%, and the average occurrence time of pressure ulcers was pushed back from fourth day to sixth day. Moreover, the dressing reduces costs. Nair [20] used polyurethane foam dressings to treat varicose ulcers in two patients and found that they reduced the pain during dressing change, were easy to use, and significantly reduced the leaking of the wound and periwound area. These findings are consistent with our study findings.

The mechanism of action of the polyurethane dressing is as follows: (1) it provides a moderately humid and air-tight environment to keep tissues in a low-oxygen environment, such that macrophages and polymorphonuclear cells release a variety of growth factors; (2) it provides continuous local insulation to avoid external cold stimulation, relieve vascular spasm, promote local blood circulation, promote the repair of damaged blood vessels and tissues, and promote the formation of capillaries; (3) it forms a slightly acidic environment, inhibiting bacterial growth, promoting white blood cell proliferation, and repairing damaged blood vessels and tissues; (4) it retains macrophages, white blood cells, and growth factors in the exudate, thereby accelerating tissue repair, protecting nerve endings, and reducing local pain [21]. In addition, Rossi et al. studied 41 active ulcers in patients with systemic sclerosis and found that patients who used the polyurethane foam dressings had a significantly lower average length of stay and better quality of life than those who used standard therapies [21]. Based on these studies, we used polyurethane foam dressings to effectively prevent local reactions such as subcutaneous induration and rash caused by azacitidine and shorten the duration of local pain and adverse reactions, while reducing pain and avoiding treatment interruptions caused by severe skin reactions.

Limitations

This study had some limitations. First, this was a single-center prospective study with a small sample size; a multicenter prospective cohort study with a large sample size and same objectives should be conducted. Second, we only analyzed pre-discharge results and did not follow up with patients after discharge. Therefore, the long-term effects of polyurethane foam dressings in preventing local adverse reactions to azacitidine subcutaneous injection could not be assessed.

Conclusion

Azacitidine is a new drug used in the management of MDS and AML. Coping with its associated non-hematological toxic reactions is an area of focus. The application of polyurethane foam dressings to the azacitidine injection site effectively reduces local skin adverse reactions, reduces local pain, and improves the patient’s medical experience. Their clinical use should be encouraged.

Authorship

YW, CC, YL (Yanfang Lin), MC, JC, XC, SC, XH and YL (Yanjuan Lin) designed the research. YW and CC were responsible for trial execution and data collection under the supervision of YL (Yanjuan Lin), XH, MC, JC, XC, SC and YL (Yanfang Lin). YL (Yanfang Lin), MC and JC provided access to potential study participants and facilitated study recruitment. XC, SC and MH analyzed data. YW, CC, and MC wrote the first draft of the manuscript, which and MH were critically reviewed and improved by all authors. YL (Yanjuan Lin) and XH were responsible for the final content. All authors read and approved the final manuscript.

Acknowledgements

We thank all the participants and their relatives for their consent to participate in this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Malignant Hematology Diagnosis and Treatment Team Talent Highland Construction Project (010102309) and sponsored by the National and Fujian Provincial Key Clinical Specialty Discipline Construction Program, P. R. C.