Resina Draconis as a topical treatment for pressure ulcers: A systematic review and meta-analysis Jiaqi Xu, BMed, RN; Tian Xiong, MMEd, RN; Ying Yang, BMed; Jie Li, PhD, RN; Jing Mao, MD, PhD School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Reprint requests: Jie Li, School of Nursing, 13 Hangkong Road, Wuhan, Hubei, China. Tel: 186 18971097091; Fax: 186 02783692635; Email: [email protected], Jing Mao, School of Nursing, 13 Hangkong Road, Wuhan, Hubei, China. Tel: 186 15927451058; Fax: 186 02783692635; Email: [email protected] Manuscript received: November 28, 2014 Accepted in final form: May 1, 2015 DOI:10.1111/wrr.12314
ABSTRACT In recent years, a number of studies have reported on Resina Draconis (RD) as a topical treatment for pressure ulcers. To evaluate these studies, we performed a systematic review and meta-analysis aimed to examine the efficacy of RD for pressure ulcers. We searched eight electronic databases to identify randomized controlled trials in which RD treatment was compared with other topical treatment of pressure ulcers from 1980 to 2014. Selection of studies, study appraisal, data extraction and analysis were undertaken using standard methods. Fourteen randomized controlled trials were included involving 618 patients. The results of the meta-analysis showed that, RD treatment was significantly associated with a higher healing rate for pressure ulcers (risk ratio 2.07, 95% confidence intervals 1.73–2.48, p < 0.001). The results of descriptive analysis showed that, compared with the control group, RD treatment shortened healing time. As for safety, adverse reactions had not been reported. These results suggest that RD can improve the healing rate for pressure ulcers and shorten the healing time, compared with other topical treatments. However, due to limited quality and quantity of the included studies, this conclusion needs to be proved by more high quality studies.
Pressure ulcers are localized injuries to the skin and/or underlying tissue that usually occur in those who cannot reposition themselves to relieve pressure on their bony prominences. It is well acknowledged that pressure ulcers are often caused by pressure, shear, friction, or a combination of these. Prolonged exposure to pressures just slightly above capillary filling pressure leads to inflow impairment and resultant local ischemia and tissue damage. The common sites for pressure ulcers are elbow, heel, hip, shoulder, back, and back of the head. Development of pressure ulcers cause patient’s severe emotional and physical stress and increased caregiver’s burden, which in turn, significantly influenced patient’s quality of life. Over past 30 years, healthcare providers have been concerned with pressure ulcers and related problems because of the high incidence, long-term duration and high cost in treatment. It was reported that the prevalence rates ranged from 4.7 to 32.1% for hospital populations and up to 22% in nursing-home populations.1 In 2011, the Agency for Healthcare Research and Quality (AHRQ) reported that there are over 2,500,000 patients with pressure ulcers annually in United States.2 It was estimated the prevalence of pressure ulcers is 5–10% all over the world.3 In China, the prevalence of pressure ulcers across studies varies from 2.7 to 38%.4 Although pressure ulceration is preventable, some high-risk patients can develop skin breakdown very quickly. In the United States, pressure ulcer treatment ranges from $15,000 to $90,000 per ulcer,5 with total annual costs as high as $11 billion.6 In 2006–2007, the expenditure of wound care in UK was £9.89 million. The cost of treating a pressure ulcer varied from £1214 (grade I) to £14,108 (grade IV).7 C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
There are a variety of management approaches for pressure ulcers, including support surfaces,8 local wound applications,9 surgical interventions,10 and nutritional supplementation11 and so on. However, a systematic review identified that the use of several of these strategies in pressure ulcer treatment remains uncertain.9 Traditional Chinese medicine (TCM) has been used in healing pressure ulcers for a long time. Wound care providers have tried several herbs to treat pressure ulcers in China. Moisture burn ointment (MBO), which consists of coptis, golden cypress, scutellaria baicalensis, pberetima, and pericarpium papaveris, was initially used in burn wound. Xiao-lu Qian and colleagues demonstrated the effectiveness of MBO in healing pressure ulcers.8 Their study showed 75% of pressure ulcers healed completely within 25 days. Yang suggested that a mixed herb powder, including fossil fragments, calamine, and other substances, improved healing of pressure ulcers.
AHRQ CI MBO MD NPUAP RCT RD RR PRISMA TCM
Agency for Healthcare Research and Quality Confidence intervals Moisture burn ointment Mean difference National pressure ulcer advisory panel Randomized clinical trial Resina Draconis Risk ratio Preferred reporting items for systematic reviews and meta-analyses Traditional Chinese medicine
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The healing time of 27 patients with 51 ulcers ranged from 13 to 45 days.12 TCM believes the pathogenesis of pressure ulcers is theoretically caused by “inner heat and dampness pathogen.” First, elimination of abundant perspiration is limited; then heat toxins are transferred from inner body to skin, which makes blood viscous, disturbing the smooth flow of blood, thus causing blood stasis. When blood stasis and dampness pathogen interact with each other, it inhibits the circulation of defensive energy, leading to inflammation with local skin and progressively forming an ulcer. Accordingly, the damaged tissues in ulcers are the main factor contributing to the pathogenic progression of pressure ulcers. In TCM perspective, strategies for systemic treatment of pressure ulcers include removing necrotic tissues, clearing away heat, dispersing blood stasis, and tonification. Resina Draconis (RD), a Chinese herb, is the resin extracted from tree-stem of Dracaena cochinchinensis (Lour.), growing in Yunnan and Guangxi provinces in China. It was discovered by Cai and Xu in 1979 that it could serve as a substitute for dragon’s blood, a precious crude medicine recoded in the official Chinese pharmacopoeia.13 Modern pharmacological studies have found that RD contains a variety of active ingredients such as flavonoids, triterpenoids, glycosides, stilbenes, organic acids, phenols, and esters.14 It possesses hemostatic activity, some analgesic effect, vasoactive-antithrombotic potency,15 immunomodulatory activity and wound-healing properties.16 RD has been frequently used in China, with the effects of promoting blood circulation to remove blood stasis, relieving swelling and pain, and replenishing blood. Multiple diseases, such as cardiovascular disease,17 pressure ulcers,18 and gynecological diseases19 can be treated with RD. A large volume of literature reported that topical application of RD was effective in treating pressure ulcers.18,20 Indeed, several small sample studies conducted in Chinese population treated pressure ulcers with RD successfully. However, the efficacy of RD was still uncertain. To our knowledge, no systematic reviews or metaanalysis had focused on the use of RD in the treatment of pressure ulcers. The purpose of this study is to examine whether RD is effective in treating pressure ulcers and the length of the time to recovery using RD.
Xu et al.
ever, studies with duplication, insufficient information, mixed intervention, and crossover design were excluded. Search strategy
The online databases of The Cochrane Library, PubMed, Elsevier, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals and WanFang Data were searched from inception through July 2014 for eligible RCTs. Complex search strategies were formulated using the following terms: pressure ulcer, TCM, Chinese herbal medicine, herbal medicine, treatment, RD, and dragon’s blood. We also checked the references and citations of eligible studies from the potential eligible articles to ensure that no clinical trials were missed. Data extraction
Two reviewers (JQX and TX) independently screened titles of all articles obtained. The abstract of any study that was potentially relevant to the topic was reviewed; a full text was read when the information was inadequate from the abstract. Discrepancies were resolved by consensus after discussion with a third reviewer. The following information was collected from each available study: study characteristics (such as first author’s name, publication year, and sample size), participant characteristics (age, gender and the grade of pressure ulcer), study methods (interventions in each group), and endpoints assessments. Data from the included RCTs were extracted into prepared data extraction tables. If data were missing from reports, the authors were contacted to seek clarification and obtain any further available information. Risk of bias assessment
Risk of bias in trials was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.22 Two reviewers (JQX and JL) independently assigned a value of “high,” “low,” or “unclear” to the following domains: sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting, and other source of bias.
MATERIALS AND METHODS The procedures performed in this systematic review are in accordance with recent guidelines for the reporting of Systematic Reviews and Meta-Analysis (PRISMA guidelines).21 Inclusion criteria
Articles fulfilling the following criteria were selected for this review: (a) randomized clinical trial (RCT) study design; (b) studies without limitation of language, type of publication and whether or not a blind method was present; (c) participants of any age with pressure ulcers belonged to the I–IV phase; (d) aimed to compare the efficacy of topical application of RD with other dressings or topical agents for treating pressure ulcers; (e) available information on clinical efficacy or safety endpoints (e.g., proportion of participants with completely healed wounds, time to complete wound healing, adverse events). How566
Statistical analysis
To evaluate the efficacy of topical treatment with RD for participants with pressure ulcers, risk ratio (RRs) and mean difference (MD), both with 95% confidence intervals (CIs), were calculated using pooled group and subgroup data from the studies. Heterogeneity among studies was examined with Chi-square–based Q test and I2 statistics. p < 0.1 was considered statistically significant for heterogeneity. Degree of heterogeneity is reported according to the I2 statistics, which refers to the degree of total variation between studies (I2 < 25%, no heterogeneity; I2 5 25– 50%, moderate heterogeneity; I2 > 50%, extreme heterogeneity).23 Data pooling was performed using the fixed effects model or the random effects model. The random effects model was used if heterogeneity existed between the studies; if not, the fixed effects model was used. Publication bias was qualitatively assessed using funnel plot C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
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method. All statistical analyses were performed with the Review Manager 5.2 software.
RESULTS Study selection
Results from our literature search were detailed in Figure 1. A total of 541 studies were identified, and the titles and abstracts were reviewed for initial screening based on the described search strategies. Thirty-three potentially relevant studies were chosen for a detailed review, and 14 studies met the inclusion and exclusion criteria. Characteristics of included studies
Overall, 14 studies with 618 participants were included in this review. The study results were published between 2002 and 2013 and had sample sizes ranging from 28 to 78 participants. The experimental and control groups were relatively similar in terms of age, gender, disease category, nutritional status, and grade of pressure ulcers across all 14 studies. The demographic, clinical and therapeutic characteristics of each study were summarized in Table 1. Of the enrolled 14 studies, two classified pressure ulcers according to the national pressure ulcer advisory panel (NPUAP) grading system,38 five according to the classification in Fundamentals of Nursing39 and the rest with no clear grading system reported. All studies reported either proportion of participants with completely healed wound and/or mean time to healing. Risk of bias assessment
In general, the included studies had significant risk of bias (Table 2). Very limited information was available in many studies to permit a judgment of whether the risk of bias existed. All the included studies were described as randomized controlled trials, but only two studies29,35 described the method of sequence generation with random number table. All trials were active-controlled trials, while none of them reported any allocation concealment or methods of blinding. And because of the different formulation of RD and control intervention, it was not likely to conduct blinding either to investigator or to patients. However, the included studies had addressed all outcome data. Selective reporting was unclear because we could not access to the protocols of the included studies. Clinical Efficacy
Rate of healing Eleven studies, including 502 participants were included in this analysis. No statistical heterogeneity was observed among studies (v2 5 10.97, p 5 0.36, I2 5 9%). A metaanalysis showed that RD had encouraging therapeutic effects compared to other dressings on healing rate (RR 2.07, 95% CI 1.73–2.48, p < 0.001) (Figure 2). Three studies27,31,35 could not be pooled because the data for healing rate was not available. Due to the observed heterogeneity across studies, subgroup analysis was performed to explore whether the type C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
Figure 1. PRISMA diagram showing selection of studies.
of dressings in control groups, and the type of RD treatment influenced the efficacy of RD therapy. As shown in Figure 3, three studies compared RD treatment with disinfectant treatment, three studies compared RD treatment with antibiotic treatment, and four studies compared RD treatment with combination antimicrobials therapies. All studies provided evidence for the role of RD in promoting the healing of pressure ulcers (disinfectants: RR 1.99, 95% CI: 1.42–2.80, p < 0.001; antibiotics: RR 2.20, 95% CI: 1.41–3.42, p < 0.001; combination antimicrobials: RR 2.23, 95% CI 1.67–2.98, p < 0.001). In addition, one study comparing RD vs. rb-bFGF showed that healing rate was significantly higher in the RD group than in the control group (RR 1.64, 95% CI 1.15–2.35, p < 0.05). In the subgroup analysis examining the type of RD treatment, significant difference was found both in subgroup of RD powder (RR 2.62, 95% CI 1.90–3.62, p < 0.001) and subgroup of RD Powder mixed with 75% alcohol (RR 1.85, 95% CI 1.46–2.34, p < 0.001) (Figure 4). Additionally, Chun-fang Xiao29 reported a significant higher healing rate in patients receiving treatment of RD powder mixed with vinegar and honey compared with control group (RR 1.75, 95% CI 1.01–3.04, p < 0.05). These results were consistent with the results for all studies combined. However, in one study (Chen 2009), no significant difference was found between treatment and control group. Healing time Ten studies, including 213 participants in treatment groups and 201 participants in control groups, investigated the effects of RD on time to healing of pressure ulcers. The data were not combined in a meta-analysis due to significant heterogeneity (I2 5 91%, p < 0.01). All of the 10 studies reported statistically significant shorter time required for complete wound healing in RD treatment 567
568
T: 76 C: 71
45–82 (64)
50–100 (75)
Zou, 201132
Liang, 201233
Zhang, 201234
25–65
Xiao, 200829
38–81
50–80 59–81
Lei, 200827 Yin, 200828
Huang, 201031
13–72 68–92 (74.4 6 6.1)
Gu, 200625 Su, 200626
65–78 (71)
T: 46.2 6 22.2 C: 45.5 6 18.5
Miao, 200224
Chen, 200930
Age (MA or AR)
Author, year
26/16
31/9
31/7
18/12
20/16
46/32
20/14 30/42
19/11 18/34
27/19
Gender, no. (male/female)
Table 1. The characteristics of the included studies
III§
III/IV‡
III/IV†
II/III/IV‡
II/III/IV†
II/III‡
II/III§ III/IV‡
III/IV§ II/III‡
II/III/IV§
Stage of PU*
22
20
19
15
18
39
21 36
15 26
23
T
20
20
19
15
18
39
13 36
15 26
23
C
Sample Size
RD powder mixed with 75% alcohol
RD powder mixed with 75% alcohol
RD powder (0.1–0.3 g) mixed with vinegar and honey RD powder mixed with millet wine RD powder mixed with 75% alcohol
RD powder RD powder
RD powder (0.3–0.9 g) mixed with 75% alcohol RD powder RD powder (0.3–1.2 g)
RD treatment
Vaseline or Nitrofurazone
Rifampicin powder mixed with 75% alcohol rb-bFGF
Metronidazole
Norfloxacin powder
Gentamicin 0.5% Metronidazole 1 Gentamicin MEBO 1% Ethacridine Lactate Mupirocin ointment 1 Gentamicin
0.5% Iodophor
Control
1/1–2d
1/d or 1/2d
1/d for grade 2 PU; 2/d for grade 3 and 4 PU 1/1–2d
2–3/d
3–4/d
1–2/d 2/d; reduce to 1/d or 1/2d if getting better NA 1–2/d
2–3/d
Frequency of dressings change
14
NA
28
NA
NA
21
NA 14
NA NA
NA
Duration (days)
HR, HT
HR
HR, HT
HR, HT
HR, HT
HR, HT
HR, HT HR
HR, HT HR
HR, HT
Main outcomes
Resina Draconis for pressure ulcers Xu et al.
C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
65–85 (72.8 6 3.2)
45–86
Zhou, 201236
Yan, 201337 21/19
19/9
29/23
Gender, no. (male/female)
III§
I/II/III/IV§
II/III/IV§
Stage of PU*
20
15
26
T
20
13
26
C
Sample Size
RD powder mixed with 75% alcohol RD powder mixed with normal saline RD powder (0.3–1.2 g) mixed with 75% alcohol RD powder (0.3–1.2 g)
RD treatment
0.5% Metronidazole 1 Gentamicin
Gentamicin
0.2% Ethacridine lactate
Control
2/d; reduce to 1/d or 1/2d if getting better
1–2/d; reduce to 1/d or 1/2d if getting better 1/d
Frequency of dressings change
NA
NA
NA
Duration (days)
HR
HR, HT
HT
Main outcomes
*Pressure Ulcer Grading System. † NPUAP. ‡ Fundamentals of Nursing. § No Information. MA, mean age; AR, age range; T, treatment group; C, control group; PU, pressure ulcers; RD, Resina Draconis; MEBO, moist exposed burn ointment; rb-bFGF, recombinant bovine basic fibroblast growth factor for external use; NA, not available; HR, healing rate; HT, healing time.
58–92 (74.3)
Age (MA or AR)
He, 201235
Author, year
Table 1. Continued.
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Table 2. Risk of bias assessment
Author, Year
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
Miao, 2002 Gu, 2006 Su, 2006 Yin, 2008 Lei, 2008 Xiao, 2008 Chen, 2009 Huang, 2010 Zou, 2011 Liang, 2012 Zhang, 2012 He, 2012 Zhou, 2012 Yan, 2013
? ? ? ? ? – ? ? ? ? ? – ? ?
? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 1 1 1 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 1 1 1 1
– – – – – – – – – – – – – –
? ? ? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? ? ? ? ? ?
?, unclear; –, low risk of bias; 1, high risk of bias.
group (Table 3). One study,36 which did not provide data suitable for meta-analysis, also reported that healing time is significantly shorter in treatment group, especially for participants with grade III or IV pressure ulcers. Adverse event Except for the eight studies which did not provide available information on adverse events, the rest of the studies all reported that no adverse event occurred in any group. Publication biases The asymmetric funnel plot of the 11 studies showed that there was a publication bias (Figure 5). The small sample size, negative, and unpublished studies might be the reasons of publication bias in this study.
DISCUSSION RD has long been used as a traditional Chinese herbal medicine, and is currently used to treat wounds, ulcers and rheumatism, tumors, insect bites, and other conditions.40 However, little is known about the effect of RD as a topical treatment for pressure ulcers. This review aimed to assess the best evidence available in the literature to elucidate the benefits of RD for pressure ulcers. Results from this review demonstrated that RD treatment was associated with significantly higher healing rate for pressure ulcers, as well as presenting a shorter time for wound healing. In subgroup analysis, the healing rate in all subgroups is in favor of the RD group without exception. More specifically, RD treatment provides an advantage over
Figure 2. Forest plot showing the effect of RD on healing rate of pressure ulcers.
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Figure 3. Subgroup analyses on basis of different dressings in control groups.
conventional antimicrobial therapy and rb-bFGF therapy in promoting the healing of pressure ulcers. Furthermore, topical treatment with either RD powder alone or mixed with 75% alcohol has significant beneficial effects over other topical care in healing rate for pressure ulcers. As for safety, adverse reactions had not been reported. However, several potential limitations should be mentioned regarding the present meta-analysis. First, methodological quality of the studies was poor. All studies claimed to be RCTs, but only two studies stated the detailed methods of random sequence generation. Furthermore, no studies described allocation concealment in details. None of the studies described blinding of participants or blinding of outcome assessment, which might led to performance bias and detection bias. In addition, no protocol was available to confirm that studies were free of selective reporting bias. These different types of bias could, therefore, have led to false-positive results. Second, heterogeneity was observed between studies. Five studies reported a dose range of RD powder used in the treatment, while other studies reported that specific dosage was based on the C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
wound size. Therefore, we were unable to analysis the impact of dose on therapeutic effect. Four studies reported on the follow-up duration, while the others did not mention them. The different lengths of follow-up duration, which made the final evaluation point of curative effect not unified, might affect the results of this study. Third, limited outcomes were reported, especially with regard to adverse events and prognosis. Only six studies mentioned adverse events, indicating an incomplete evaluation of the safety of RD treatment, as well as poor quality of reporting. None of the studies reported a follow-up period after treatment. Therefore, we were unable to adequately assess the safety of RD for pressure ulcers. Last but not least, funnel plot indicated that publication and other biases might play an important role, because all of the studies were performed in China, where they have appeared to produce almost no negative findings. In addition, all the included studies were not multicenter, large scale RCTs. Meta-analysis is retrospective research that is subject to some methodological limitations. To minimize the bias, we used explicit methods for study selection, data 571
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Figure 4. Subgroup analyses on basis of RD treatment.
extraction and data analysis. Nevertheless, our results should be interpreted with caution. Our findings that RD has encouraging therapeutic effects for pressure ulcers compared with other dressings
are inline with those of an earlier meta-analysis on therapeutic effect of TCM conducted by Qian.41 Similarly, in a pharmacological study evaluating the wound healing potential of RD, Liu16 reported a significant reduction in wound size and mean epithelization time as well as the higher expression of growth factors in the RD treated group. Regarding adverse effects, our finding is also in agreement with a toxicology study conducted by Zeng.42 No major toxicity has been reported from RD. The American Products Association lists RD as Class I, meaning it can be consumed safely when used appropriately. Recent pharmaceutical toxicology study showed that gavaging the mice with clinical daily dose of RD (0.072 g/kg) 150 times continuously for 30 days caused no toxic reactions. Relevance to clinical practice
Figure 5. Funnel plots for assessment of publication bias in the meta-analysis.
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This is the first combined systematic review and metaanalysis to examine the efficacy of RD for pressure ulcers. However, there is not enough high quality evidence available concerning the effect on pressure ulcers. Consequently, no firm recommendations can be made for topical treatment of RD in clinical practice. Further concerns C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
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Table 3. Comparison of the healing time between RD and other topical interventions in the treatment of patients with pressure ulcers RD treatment
Author, year Miao, 2002 Gu, 2006 Lei, 2008 Xiao, 2008
Control
Mean (days)
SD
Total
Mean (days)
SD
Total
MD (95% CI) (days)
15 18.5 7 7.29 17.12 8.21 21.6 12 8 10.38
6.5 2.5 2.5 1.68 2.03 2.31 3.98 2.1 0.7 2.26
23 15 21 21 26 18 22 19 22 38
43 35.5 14 11.05 19.23 12.21 47.9 20 28.5 14.24
22.5 7.5 1.5 1.88 1.45 2.52 11.12 2.2 1.5 2.56
23 15 13 20 22 18 20 19 20 34
228.00[237.57, 218.43] 217.00[221.00, 213.00] 27.00[28.34, 25.66] 23.76[24.85, 22.67] 22.11[23.10, 221.12] 24.00[25.58, 22.42] 226.30[231.45, 221.15] 28.00[29.37, 26.63] 220.50[221.22, 219.78] 23.86[24.98, 22.74]
Grade II Grade III
Chen, 2009 Huang, 2010 Zou, 2011 Zhang, 2012 He, 2012
arising from our review include the best preparation methods and doses of RD to be used.
P p p p p p p p p p p
< < < < < < < < <
Reprint requests: Jie Li, School of Nursing, 13 Hangkong Road, Wuhan, Hubei, China. Tel: 186 18971097091; Fax: 186 02783692635; Email: [email protected], Jing Mao, School of Nursing, 13 Hangkong Road, Wuhan, Hubei, China. Tel: 186 15927451058; Fax: 186 02783692635; Email: [email protected] Manuscript received: November 28, 2014 Accepted in final form: May 1, 2015 DOI:10.1111/wrr.12314
ABSTRACT In recent years, a number of studies have reported on Resina Draconis (RD) as a topical treatment for pressure ulcers. To evaluate these studies, we performed a systematic review and meta-analysis aimed to examine the efficacy of RD for pressure ulcers. We searched eight electronic databases to identify randomized controlled trials in which RD treatment was compared with other topical treatment of pressure ulcers from 1980 to 2014. Selection of studies, study appraisal, data extraction and analysis were undertaken using standard methods. Fourteen randomized controlled trials were included involving 618 patients. The results of the meta-analysis showed that, RD treatment was significantly associated with a higher healing rate for pressure ulcers (risk ratio 2.07, 95% confidence intervals 1.73–2.48, p < 0.001). The results of descriptive analysis showed that, compared with the control group, RD treatment shortened healing time. As for safety, adverse reactions had not been reported. These results suggest that RD can improve the healing rate for pressure ulcers and shorten the healing time, compared with other topical treatments. However, due to limited quality and quantity of the included studies, this conclusion needs to be proved by more high quality studies.
Pressure ulcers are localized injuries to the skin and/or underlying tissue that usually occur in those who cannot reposition themselves to relieve pressure on their bony prominences. It is well acknowledged that pressure ulcers are often caused by pressure, shear, friction, or a combination of these. Prolonged exposure to pressures just slightly above capillary filling pressure leads to inflow impairment and resultant local ischemia and tissue damage. The common sites for pressure ulcers are elbow, heel, hip, shoulder, back, and back of the head. Development of pressure ulcers cause patient’s severe emotional and physical stress and increased caregiver’s burden, which in turn, significantly influenced patient’s quality of life. Over past 30 years, healthcare providers have been concerned with pressure ulcers and related problems because of the high incidence, long-term duration and high cost in treatment. It was reported that the prevalence rates ranged from 4.7 to 32.1% for hospital populations and up to 22% in nursing-home populations.1 In 2011, the Agency for Healthcare Research and Quality (AHRQ) reported that there are over 2,500,000 patients with pressure ulcers annually in United States.2 It was estimated the prevalence of pressure ulcers is 5–10% all over the world.3 In China, the prevalence of pressure ulcers across studies varies from 2.7 to 38%.4 Although pressure ulceration is preventable, some high-risk patients can develop skin breakdown very quickly. In the United States, pressure ulcer treatment ranges from $15,000 to $90,000 per ulcer,5 with total annual costs as high as $11 billion.6 In 2006–2007, the expenditure of wound care in UK was £9.89 million. The cost of treating a pressure ulcer varied from £1214 (grade I) to £14,108 (grade IV).7 C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
There are a variety of management approaches for pressure ulcers, including support surfaces,8 local wound applications,9 surgical interventions,10 and nutritional supplementation11 and so on. However, a systematic review identified that the use of several of these strategies in pressure ulcer treatment remains uncertain.9 Traditional Chinese medicine (TCM) has been used in healing pressure ulcers for a long time. Wound care providers have tried several herbs to treat pressure ulcers in China. Moisture burn ointment (MBO), which consists of coptis, golden cypress, scutellaria baicalensis, pberetima, and pericarpium papaveris, was initially used in burn wound. Xiao-lu Qian and colleagues demonstrated the effectiveness of MBO in healing pressure ulcers.8 Their study showed 75% of pressure ulcers healed completely within 25 days. Yang suggested that a mixed herb powder, including fossil fragments, calamine, and other substances, improved healing of pressure ulcers.
AHRQ CI MBO MD NPUAP RCT RD RR PRISMA TCM
Agency for Healthcare Research and Quality Confidence intervals Moisture burn ointment Mean difference National pressure ulcer advisory panel Randomized clinical trial Resina Draconis Risk ratio Preferred reporting items for systematic reviews and meta-analyses Traditional Chinese medicine
565
Resina Draconis for pressure ulcers
The healing time of 27 patients with 51 ulcers ranged from 13 to 45 days.12 TCM believes the pathogenesis of pressure ulcers is theoretically caused by “inner heat and dampness pathogen.” First, elimination of abundant perspiration is limited; then heat toxins are transferred from inner body to skin, which makes blood viscous, disturbing the smooth flow of blood, thus causing blood stasis. When blood stasis and dampness pathogen interact with each other, it inhibits the circulation of defensive energy, leading to inflammation with local skin and progressively forming an ulcer. Accordingly, the damaged tissues in ulcers are the main factor contributing to the pathogenic progression of pressure ulcers. In TCM perspective, strategies for systemic treatment of pressure ulcers include removing necrotic tissues, clearing away heat, dispersing blood stasis, and tonification. Resina Draconis (RD), a Chinese herb, is the resin extracted from tree-stem of Dracaena cochinchinensis (Lour.), growing in Yunnan and Guangxi provinces in China. It was discovered by Cai and Xu in 1979 that it could serve as a substitute for dragon’s blood, a precious crude medicine recoded in the official Chinese pharmacopoeia.13 Modern pharmacological studies have found that RD contains a variety of active ingredients such as flavonoids, triterpenoids, glycosides, stilbenes, organic acids, phenols, and esters.14 It possesses hemostatic activity, some analgesic effect, vasoactive-antithrombotic potency,15 immunomodulatory activity and wound-healing properties.16 RD has been frequently used in China, with the effects of promoting blood circulation to remove blood stasis, relieving swelling and pain, and replenishing blood. Multiple diseases, such as cardiovascular disease,17 pressure ulcers,18 and gynecological diseases19 can be treated with RD. A large volume of literature reported that topical application of RD was effective in treating pressure ulcers.18,20 Indeed, several small sample studies conducted in Chinese population treated pressure ulcers with RD successfully. However, the efficacy of RD was still uncertain. To our knowledge, no systematic reviews or metaanalysis had focused on the use of RD in the treatment of pressure ulcers. The purpose of this study is to examine whether RD is effective in treating pressure ulcers and the length of the time to recovery using RD.
Xu et al.
ever, studies with duplication, insufficient information, mixed intervention, and crossover design were excluded. Search strategy
The online databases of The Cochrane Library, PubMed, Elsevier, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals and WanFang Data were searched from inception through July 2014 for eligible RCTs. Complex search strategies were formulated using the following terms: pressure ulcer, TCM, Chinese herbal medicine, herbal medicine, treatment, RD, and dragon’s blood. We also checked the references and citations of eligible studies from the potential eligible articles to ensure that no clinical trials were missed. Data extraction
Two reviewers (JQX and TX) independently screened titles of all articles obtained. The abstract of any study that was potentially relevant to the topic was reviewed; a full text was read when the information was inadequate from the abstract. Discrepancies were resolved by consensus after discussion with a third reviewer. The following information was collected from each available study: study characteristics (such as first author’s name, publication year, and sample size), participant characteristics (age, gender and the grade of pressure ulcer), study methods (interventions in each group), and endpoints assessments. Data from the included RCTs were extracted into prepared data extraction tables. If data were missing from reports, the authors were contacted to seek clarification and obtain any further available information. Risk of bias assessment
Risk of bias in trials was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.22 Two reviewers (JQX and JL) independently assigned a value of “high,” “low,” or “unclear” to the following domains: sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting, and other source of bias.
MATERIALS AND METHODS The procedures performed in this systematic review are in accordance with recent guidelines for the reporting of Systematic Reviews and Meta-Analysis (PRISMA guidelines).21 Inclusion criteria
Articles fulfilling the following criteria were selected for this review: (a) randomized clinical trial (RCT) study design; (b) studies without limitation of language, type of publication and whether or not a blind method was present; (c) participants of any age with pressure ulcers belonged to the I–IV phase; (d) aimed to compare the efficacy of topical application of RD with other dressings or topical agents for treating pressure ulcers; (e) available information on clinical efficacy or safety endpoints (e.g., proportion of participants with completely healed wounds, time to complete wound healing, adverse events). How566
Statistical analysis
To evaluate the efficacy of topical treatment with RD for participants with pressure ulcers, risk ratio (RRs) and mean difference (MD), both with 95% confidence intervals (CIs), were calculated using pooled group and subgroup data from the studies. Heterogeneity among studies was examined with Chi-square–based Q test and I2 statistics. p < 0.1 was considered statistically significant for heterogeneity. Degree of heterogeneity is reported according to the I2 statistics, which refers to the degree of total variation between studies (I2 < 25%, no heterogeneity; I2 5 25– 50%, moderate heterogeneity; I2 > 50%, extreme heterogeneity).23 Data pooling was performed using the fixed effects model or the random effects model. The random effects model was used if heterogeneity existed between the studies; if not, the fixed effects model was used. Publication bias was qualitatively assessed using funnel plot C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
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method. All statistical analyses were performed with the Review Manager 5.2 software.
RESULTS Study selection
Results from our literature search were detailed in Figure 1. A total of 541 studies were identified, and the titles and abstracts were reviewed for initial screening based on the described search strategies. Thirty-three potentially relevant studies were chosen for a detailed review, and 14 studies met the inclusion and exclusion criteria. Characteristics of included studies
Overall, 14 studies with 618 participants were included in this review. The study results were published between 2002 and 2013 and had sample sizes ranging from 28 to 78 participants. The experimental and control groups were relatively similar in terms of age, gender, disease category, nutritional status, and grade of pressure ulcers across all 14 studies. The demographic, clinical and therapeutic characteristics of each study were summarized in Table 1. Of the enrolled 14 studies, two classified pressure ulcers according to the national pressure ulcer advisory panel (NPUAP) grading system,38 five according to the classification in Fundamentals of Nursing39 and the rest with no clear grading system reported. All studies reported either proportion of participants with completely healed wound and/or mean time to healing. Risk of bias assessment
In general, the included studies had significant risk of bias (Table 2). Very limited information was available in many studies to permit a judgment of whether the risk of bias existed. All the included studies were described as randomized controlled trials, but only two studies29,35 described the method of sequence generation with random number table. All trials were active-controlled trials, while none of them reported any allocation concealment or methods of blinding. And because of the different formulation of RD and control intervention, it was not likely to conduct blinding either to investigator or to patients. However, the included studies had addressed all outcome data. Selective reporting was unclear because we could not access to the protocols of the included studies. Clinical Efficacy
Rate of healing Eleven studies, including 502 participants were included in this analysis. No statistical heterogeneity was observed among studies (v2 5 10.97, p 5 0.36, I2 5 9%). A metaanalysis showed that RD had encouraging therapeutic effects compared to other dressings on healing rate (RR 2.07, 95% CI 1.73–2.48, p < 0.001) (Figure 2). Three studies27,31,35 could not be pooled because the data for healing rate was not available. Due to the observed heterogeneity across studies, subgroup analysis was performed to explore whether the type C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
Figure 1. PRISMA diagram showing selection of studies.
of dressings in control groups, and the type of RD treatment influenced the efficacy of RD therapy. As shown in Figure 3, three studies compared RD treatment with disinfectant treatment, three studies compared RD treatment with antibiotic treatment, and four studies compared RD treatment with combination antimicrobials therapies. All studies provided evidence for the role of RD in promoting the healing of pressure ulcers (disinfectants: RR 1.99, 95% CI: 1.42–2.80, p < 0.001; antibiotics: RR 2.20, 95% CI: 1.41–3.42, p < 0.001; combination antimicrobials: RR 2.23, 95% CI 1.67–2.98, p < 0.001). In addition, one study comparing RD vs. rb-bFGF showed that healing rate was significantly higher in the RD group than in the control group (RR 1.64, 95% CI 1.15–2.35, p < 0.05). In the subgroup analysis examining the type of RD treatment, significant difference was found both in subgroup of RD powder (RR 2.62, 95% CI 1.90–3.62, p < 0.001) and subgroup of RD Powder mixed with 75% alcohol (RR 1.85, 95% CI 1.46–2.34, p < 0.001) (Figure 4). Additionally, Chun-fang Xiao29 reported a significant higher healing rate in patients receiving treatment of RD powder mixed with vinegar and honey compared with control group (RR 1.75, 95% CI 1.01–3.04, p < 0.05). These results were consistent with the results for all studies combined. However, in one study (Chen 2009), no significant difference was found between treatment and control group. Healing time Ten studies, including 213 participants in treatment groups and 201 participants in control groups, investigated the effects of RD on time to healing of pressure ulcers. The data were not combined in a meta-analysis due to significant heterogeneity (I2 5 91%, p < 0.01). All of the 10 studies reported statistically significant shorter time required for complete wound healing in RD treatment 567
568
T: 76 C: 71
45–82 (64)
50–100 (75)
Zou, 201132
Liang, 201233
Zhang, 201234
25–65
Xiao, 200829
38–81
50–80 59–81
Lei, 200827 Yin, 200828
Huang, 201031
13–72 68–92 (74.4 6 6.1)
Gu, 200625 Su, 200626
65–78 (71)
T: 46.2 6 22.2 C: 45.5 6 18.5
Miao, 200224
Chen, 200930
Age (MA or AR)
Author, year
26/16
31/9
31/7
18/12
20/16
46/32
20/14 30/42
19/11 18/34
27/19
Gender, no. (male/female)
Table 1. The characteristics of the included studies
III§
III/IV‡
III/IV†
II/III/IV‡
II/III/IV†
II/III‡
II/III§ III/IV‡
III/IV§ II/III‡
II/III/IV§
Stage of PU*
22
20
19
15
18
39
21 36
15 26
23
T
20
20
19
15
18
39
13 36
15 26
23
C
Sample Size
RD powder mixed with 75% alcohol
RD powder mixed with 75% alcohol
RD powder (0.1–0.3 g) mixed with vinegar and honey RD powder mixed with millet wine RD powder mixed with 75% alcohol
RD powder RD powder
RD powder (0.3–0.9 g) mixed with 75% alcohol RD powder RD powder (0.3–1.2 g)
RD treatment
Vaseline or Nitrofurazone
Rifampicin powder mixed with 75% alcohol rb-bFGF
Metronidazole
Norfloxacin powder
Gentamicin 0.5% Metronidazole 1 Gentamicin MEBO 1% Ethacridine Lactate Mupirocin ointment 1 Gentamicin
0.5% Iodophor
Control
1/1–2d
1/d or 1/2d
1/d for grade 2 PU; 2/d for grade 3 and 4 PU 1/1–2d
2–3/d
3–4/d
1–2/d 2/d; reduce to 1/d or 1/2d if getting better NA 1–2/d
2–3/d
Frequency of dressings change
14
NA
28
NA
NA
21
NA 14
NA NA
NA
Duration (days)
HR, HT
HR
HR, HT
HR, HT
HR, HT
HR, HT
HR, HT HR
HR, HT HR
HR, HT
Main outcomes
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C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
65–85 (72.8 6 3.2)
45–86
Zhou, 201236
Yan, 201337 21/19
19/9
29/23
Gender, no. (male/female)
III§
I/II/III/IV§
II/III/IV§
Stage of PU*
20
15
26
T
20
13
26
C
Sample Size
RD powder mixed with 75% alcohol RD powder mixed with normal saline RD powder (0.3–1.2 g) mixed with 75% alcohol RD powder (0.3–1.2 g)
RD treatment
0.5% Metronidazole 1 Gentamicin
Gentamicin
0.2% Ethacridine lactate
Control
2/d; reduce to 1/d or 1/2d if getting better
1–2/d; reduce to 1/d or 1/2d if getting better 1/d
Frequency of dressings change
NA
NA
NA
Duration (days)
HR
HR, HT
HT
Main outcomes
*Pressure Ulcer Grading System. † NPUAP. ‡ Fundamentals of Nursing. § No Information. MA, mean age; AR, age range; T, treatment group; C, control group; PU, pressure ulcers; RD, Resina Draconis; MEBO, moist exposed burn ointment; rb-bFGF, recombinant bovine basic fibroblast growth factor for external use; NA, not available; HR, healing rate; HT, healing time.
58–92 (74.3)
Age (MA or AR)
He, 201235
Author, year
Table 1. Continued.
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Table 2. Risk of bias assessment
Author, Year
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
Miao, 2002 Gu, 2006 Su, 2006 Yin, 2008 Lei, 2008 Xiao, 2008 Chen, 2009 Huang, 2010 Zou, 2011 Liang, 2012 Zhang, 2012 He, 2012 Zhou, 2012 Yan, 2013
? ? ? ? ? – ? ? ? ? ? – ? ?
? ? ? ? ? ? ? ? ? ? ? ? ? ?
1 1 1 1 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 1 1 1 1
– – – – – – – – – – – – – –
? ? ? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? ? ? ? ? ?
?, unclear; –, low risk of bias; 1, high risk of bias.
group (Table 3). One study,36 which did not provide data suitable for meta-analysis, also reported that healing time is significantly shorter in treatment group, especially for participants with grade III or IV pressure ulcers. Adverse event Except for the eight studies which did not provide available information on adverse events, the rest of the studies all reported that no adverse event occurred in any group. Publication biases The asymmetric funnel plot of the 11 studies showed that there was a publication bias (Figure 5). The small sample size, negative, and unpublished studies might be the reasons of publication bias in this study.
DISCUSSION RD has long been used as a traditional Chinese herbal medicine, and is currently used to treat wounds, ulcers and rheumatism, tumors, insect bites, and other conditions.40 However, little is known about the effect of RD as a topical treatment for pressure ulcers. This review aimed to assess the best evidence available in the literature to elucidate the benefits of RD for pressure ulcers. Results from this review demonstrated that RD treatment was associated with significantly higher healing rate for pressure ulcers, as well as presenting a shorter time for wound healing. In subgroup analysis, the healing rate in all subgroups is in favor of the RD group without exception. More specifically, RD treatment provides an advantage over
Figure 2. Forest plot showing the effect of RD on healing rate of pressure ulcers.
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Figure 3. Subgroup analyses on basis of different dressings in control groups.
conventional antimicrobial therapy and rb-bFGF therapy in promoting the healing of pressure ulcers. Furthermore, topical treatment with either RD powder alone or mixed with 75% alcohol has significant beneficial effects over other topical care in healing rate for pressure ulcers. As for safety, adverse reactions had not been reported. However, several potential limitations should be mentioned regarding the present meta-analysis. First, methodological quality of the studies was poor. All studies claimed to be RCTs, but only two studies stated the detailed methods of random sequence generation. Furthermore, no studies described allocation concealment in details. None of the studies described blinding of participants or blinding of outcome assessment, which might led to performance bias and detection bias. In addition, no protocol was available to confirm that studies were free of selective reporting bias. These different types of bias could, therefore, have led to false-positive results. Second, heterogeneity was observed between studies. Five studies reported a dose range of RD powder used in the treatment, while other studies reported that specific dosage was based on the C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
wound size. Therefore, we were unable to analysis the impact of dose on therapeutic effect. Four studies reported on the follow-up duration, while the others did not mention them. The different lengths of follow-up duration, which made the final evaluation point of curative effect not unified, might affect the results of this study. Third, limited outcomes were reported, especially with regard to adverse events and prognosis. Only six studies mentioned adverse events, indicating an incomplete evaluation of the safety of RD treatment, as well as poor quality of reporting. None of the studies reported a follow-up period after treatment. Therefore, we were unable to adequately assess the safety of RD for pressure ulcers. Last but not least, funnel plot indicated that publication and other biases might play an important role, because all of the studies were performed in China, where they have appeared to produce almost no negative findings. In addition, all the included studies were not multicenter, large scale RCTs. Meta-analysis is retrospective research that is subject to some methodological limitations. To minimize the bias, we used explicit methods for study selection, data 571
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Figure 4. Subgroup analyses on basis of RD treatment.
extraction and data analysis. Nevertheless, our results should be interpreted with caution. Our findings that RD has encouraging therapeutic effects for pressure ulcers compared with other dressings
are inline with those of an earlier meta-analysis on therapeutic effect of TCM conducted by Qian.41 Similarly, in a pharmacological study evaluating the wound healing potential of RD, Liu16 reported a significant reduction in wound size and mean epithelization time as well as the higher expression of growth factors in the RD treated group. Regarding adverse effects, our finding is also in agreement with a toxicology study conducted by Zeng.42 No major toxicity has been reported from RD. The American Products Association lists RD as Class I, meaning it can be consumed safely when used appropriately. Recent pharmaceutical toxicology study showed that gavaging the mice with clinical daily dose of RD (0.072 g/kg) 150 times continuously for 30 days caused no toxic reactions. Relevance to clinical practice
Figure 5. Funnel plots for assessment of publication bias in the meta-analysis.
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This is the first combined systematic review and metaanalysis to examine the efficacy of RD for pressure ulcers. However, there is not enough high quality evidence available concerning the effect on pressure ulcers. Consequently, no firm recommendations can be made for topical treatment of RD in clinical practice. Further concerns C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 565–574 V
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Table 3. Comparison of the healing time between RD and other topical interventions in the treatment of patients with pressure ulcers RD treatment
Author, year Miao, 2002 Gu, 2006 Lei, 2008 Xiao, 2008
Control
Mean (days)
SD
Total
Mean (days)
SD
Total
MD (95% CI) (days)
15 18.5 7 7.29 17.12 8.21 21.6 12 8 10.38
6.5 2.5 2.5 1.68 2.03 2.31 3.98 2.1 0.7 2.26
23 15 21 21 26 18 22 19 22 38
43 35.5 14 11.05 19.23 12.21 47.9 20 28.5 14.24
22.5 7.5 1.5 1.88 1.45 2.52 11.12 2.2 1.5 2.56
23 15 13 20 22 18 20 19 20 34
228.00[237.57, 218.43] 217.00[221.00, 213.00] 27.00[28.34, 25.66] 23.76[24.85, 22.67] 22.11[23.10, 221.12] 24.00[25.58, 22.42] 226.30[231.45, 221.15] 28.00[29.37, 26.63] 220.50[221.22, 219.78] 23.86[24.98, 22.74]
Grade II Grade III
Chen, 2009 Huang, 2010 Zou, 2011 Zhang, 2012 He, 2012
arising from our review include the best preparation methods and doses of RD to be used.
P p p p p p p p p p p
< < < < < < < < <
