Keywords
Chronic wounds; hemoglobin spray, hyperbaric oxygen therapy, topical hemoglobin therapy, wound management
-
Views
-
Downloads
How to cite this article
Wilasrusmee C, Supsamutchai C, Pornwaragorn C et al. The efficacy of hemoglobin spray in wound management: a systematic review and network meta-analysis of comparative studies [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:1265 (https://doi.org/10.12688/f1000research.148208.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
Export Citation
Sciwheel
EndNote
Ref. Manager
Bibtex
ProCite
Sente
▬
✚
Systematic Review
The efficacy of hemoglobin spray in wound management: a systematic review and network meta-analysis of comparative studies
[version 1; peer review: awaiting peer review]
PUBLISHED 22 Oct 2024
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Global Public Health gateway.
Abstract
Corresponding author:
Napaphat Poprom
Competing interests:
No competing interests were disclosed.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2024 Wilasrusmee C et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Wilasrusmee C, Supsamutchai C, Pornwaragorn C et al. The efficacy of hemoglobin spray in wound management: a systematic review and network meta-analysis of comparative studies [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:1265 (https://doi.org/10.12688/f1000research.148208.1)
First published: 22 Oct 2024, 13:1265 (https://doi.org/10.12688/f1000research.148208.1)
Latest published: 22 Oct 2024, 13:1265 (https://doi.org/10.12688/f1000research.148208.1)
Introduction
Non-healing wounds are a global problem about 2–6% of the a whole population.1 Among types of wound, the chronic wounds were fail to heal after 2–4 weeks of standard care and require further intervention.2 The most common sub-types of chronic wounds generally fall into four categories: venous leg ulcers (VLUs), pressure ulcers (PUs), diabetic foot ulcers (DFUs), and leg ulcers associated with arterial insufficiency. Chronic wounds also result from trauma, surgery or burns.3 The standard of care fails to heal approximately 25 and 50% of venous leg ulcers and diabetic foot ulcers, respectively.4 Thus, there is an unmet need for novel therapies that promote healing and more efficient wound care in complex, difficult-to-heal wounds.
Oxygen and an adequate blood supply are potentially effective interventions for chronic wounds. Restoration of macro- and micro-circulation is essential for the oxygen delivery needed for defenses against pathogens and reconstruction of new vessels and connective tissue. Tissue hypoxia may be a common etiology for the pathological mechanisms underlying wound healing disorders.5
Hyperbaric oxygen therapy (HBOT) is the treatment from 100% oxygen at specific one atmosphere pressures with period of time and HBOT has been reported about the effective for diabetic foot ulcers patients.6 It significantly reduces the risk of major amputation and improves the chance of healing at 1 year.7 However, previous clinical trials and systematic reviews on the effectiveness of HBOT have shown conflicting evidence regarding the efficacy of HBOT in the treatment of chronic wounds.8 In people with foot ulcers due to diabetes, HBOT might significantly improve ulcer healing in the short term, but not in the long term, and reports have various flaws in design and/or reporting.9 The overall positive effect of improvement in oxygen supply on wound healing remains controversial.
Topical hemoglobin therapy (hemoglobin spray), a novel therapeutic technology, has been approved as an effective delivery method for improving oxygenation in chronic wounds. Transudates and exudates are significant barriers to the diffusion of oxygen into the tissue in the wound bed. Topical hemoglobin spraying aims to use the effects of the diffusion of oxygen into the wound bed. The mechanism of hemoglobin spray, which comprises purified hemoglobin, is based on the use of hemoglobin as an oxygen carrier, which improves the availability of oxygen in the wound by binding atmospheric oxygen and transportation of oxygen. Recent studies have demonstrated that it is effective in promoting wound healing and reducing inflammation, exudates, and slough.10–12
However, there is no evidence to compare the treatment results of hemoglobin spray and HBOT. Therefore, we conducted a systematic review and network meta-analysis to explore the efficacy and role of hemoglobin spray in the treatment of chronic wounds. The probabilities of being the best treatment option, that is, high efficacy and safety, were estimated and ranked between hemoglobin spray and HBOT.
Methods
A systematic review and network meta-analysis (NMA) was conducted following the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA [Extended Data]43) guidelines and PROSPERO number CRD42020161396.
Literature and search strategy
Studies were identified according to the PICO by using two major databases composed of MEDLINE and SCOPUS from inception to June 2020 and generated the search following by PICO that separates into sub-domain and combines within sub-domain and within domain by using “or” another between domain combine by using “and” as described in (supplementary Tables s1a and s1b [Extended Data]44).
Study selection
Randomized controlled trials (RCTs) and observational studies published in English were selected if they met all the following criteria: 1) studies in adult patients who were diagnosed with chronic wound, wound infection, diabetic wound, post-traumatic wound, and venous ulcer; 2) compared effects of any pair of interventions including hemoglobin spray, hyperbaric, and standard care; 3) reported at least one of the following outcomes of interest: wound healing, wound size reduction, reduction of fever, discomfort, pain, prevention of surgical size infection, faster granulation or epithelialization, reduction of surrounding edema or erythema, better cosmetic results, reduction in antibiotic use, and reduction of hospital stay.
Two researchers independently selected the studies by screening titles and abstracts. If a decision could not be made, the full text was retrieved and reviewed. Any disagreement was resolved by consensus and adjudication by a third author.
Interventions and outcomes of interests
Interventions included topical hemoglobin therapy (hemoglobin spray), hyperbaric oxygen therapy, and standard care.
Outcomes were including: wound healing, wound size reduction, healing time.
Data extraction
Three reviewers (CW, JJ, and CS) independently selected studies by screening titles and abstracts. If a decision could not be made, the full text was retrieved and reviewed. Any disagreement was resolved by consensus with adjudication by a third author (SH or CP).
Risk of bias assessments
The quality of the studies was independently assessed by CW, CP, and SH based on the recommended of the Cochrane library,13 which was graded as “yes” for low risk of bias, “no” for high risk of bias, and “unclear” if there was insufficient information to judge. Any disagreement between the reviewers was resolved by consensus.
Statistical analysis
Direct meta-analysis (DMA)
For each study, the risk ratio (RR) and mean difference (MD) along with their variances were estimated for dichotomous outcomes (i.e., wound healing, reduction of fever, discomfort, surgical size infection, granulation or epithelialization, and edema or erythema) and continuous outcomes (i.e., wound size reduction, length of hospital stay, pain, dose of antibiotic use, and satisfaction with cosmetics), respectively. The RRs and MDs were pooled across the studies.
Heterogeneity was checked using Cochran’s Q test and I2 statistic. A random-effects model and fixed-effects model were used, if appropriate. The sources of heterogeneity were explored by fitting each covariate in a meta-regression model if data were available. Subgroup analysis was performed accordingly.
Publication bias was assessed using funnel plots and Egger’s test. In cases of asymmetry, a contour-enhanced funnel plot was used to explore whether heterogeneity or publication bias was the cause of asymmetry.
Network meta-analysis (NMA)
A two-stage approach of NMA was used to estimate the relative treatment effects, including ln (RR) or MD). Binary or linear regression was used to estimate the relative treatment effects and variance-covariance for individual studies. A multivariate random-effects meta-analysis of a consistency model was used across the studies. The comparisons of mixed relative treatments were performed.
Consistency was assessed using a design-treatment interaction inconsistency model based on a global chi-square test to explore the agreement between direct and indirect comparisons. If there was any evidence of inconsistency, the characteristics of the included studies were explored and described. The probability of being the best treatment and ranking using the surface under the cumulative ranking curve (SUCRA). An adjusted funnel plot was used to assess publication bias.
All analyses were performed using STATA 16. The threshold for statistical significance was set at P < 0.05, except for heterogeneity, where P <0.1 was used.
Results
A total of 934 studies were identified from PUBMED and SCOPUS databases, and 112 articles were deleted. Among the 24 studies,12,14–36 16 RCTs14,16–20,25–30,33–36 and 8 cohort studies12,15,21–24,31,32 met our inclusion criteria (Figure 1) [Extended Data].41
Figure 1. Flow diagram of selection of studies.
Characteristics information of eligible studies
The characteristics of the 24 studies12,14–36 are described in Table 1. Among the 12 RCTs14,17–19,26–30,33,34,36 and four cohort studies23,24,31,32 included diabetes mellitus foot ulcer, another three RCTs16,20,35 and 1 cohort15 were included venous ulcer, and one RCT25 and three cohorts12,21,22 included chronic wound ulcers.
Table 1. Characteristic information of included studies.
| Author (year) | Study design | Intervention | Comparator | No. subjects | Mean age (year) | %Male | No. of healing | Mean duration of wound (month) | Types of wound | Follow-up times (weeks) |
|---|---|---|---|---|---|---|---|---|---|---|
| Arenbergerova (2013)3 | RCT | Granulox | Standard | 72 | 62 | 36 | 47 | 24 | V | 13 |
| Hammarlund (1994)7 | RCT | HBOT | Standard | 16 | 67 | 56 | 2 | NR | V | NR |
| Abidia (2003)1 | RCT | HBOT | Standard | 16 | 71 | 75 | 6 | 9 | D | 6 |
| Kessler (2003)14 | RCT | HBOT | Standard | 27 | 63.8 | 70 | 2 | >3 | D | 4 |
| Duzgun (2008)5 | RCT | HBOT | Standard | 100 | 60.7 | 62 | 33 | NR | D | NR |
| Londahl (2010)16 | RCT | HBOT | Placebo | 90 | 68.5 | 59 | 37 | 10 | D | 48 |
| Londahl (2011)17 | RCT | HBOT | Standard | 75 | 68.9 | 81 | 33 | NR | D | NR |
| Wang (2011)24 | RCT | HBOT | Standard | 77 | 61.5 | NR | 34 | NR | D | NR |
| Kaur (2012)13 | RCT | HBOT | Standard | 30 | 47.2 | 83 | 3 | 2 | C | 4.3 |
| Khandelwal (2013)15 | RCT | HBOT | Standard | 40 | 44.4 | 53 | 20 | >2 | D | 10 |
| Ma (2013)18 | RCT | HBOT | Standard | 36 | 60.1 | 64 | 11 | NR | D | NR |
| Fedorko (2016)6 | RCT | HBOT | Standard | 103 | 61.5 | 67 | 22 | NR | D | NR |
| Chen (2017)4 | RCT | HBOT | Standard | 38 | 62.6 | 55 | 6 | NR | D | NR |
| Santema (2018)22 | RCT | HBOT | Standard | 120 | 69.1 | 81 | 58 | 6 | D | 48 |
| Thistlethwaite (2018)23 | RCT | HBOT | Placebo | 30 | 70 | 50 | 12 | 18 | V | 12 |
| Salama (2019)21 | RCT | HBOT | Standard | 30 | 56.4 | 73 | 5 | NR | D | NR |
Among the 16 RCTs,14,16–20,25–30,33–36 interventions and comparators were as follows: hyperbaric versus control (N=15)14,17–20,25–30,33–36 and hemoglobin spray versus control (N=1).16 Another eight cohort studies consisted of hyperbaric versus control (N=4)21,24,31,32 and hemoglobin spray versus control (N=4)12,15,22,23 (Table 1).
Risk of bias assessment
A risk of bias assessment was performed (supplement Figure s1A [Extended Data]44). Among the 18 RCTs, all studies were considered to have a high risk of bias for blinding of outcome assessment (detection bias) and a low risk of bias for random sequence generation. Approximately 70% of RCTs had a low risk of bias for selective reporting (reporting bias), allocation concealment (selection bias), and incomplete outcome data (attrition bias). All RCTs were at a high risk of bias for blinding of participants, but this was because the participants who received the treatment could not be blinded. Another 8 observational studies suggested a low risk of bias for the study population, prognostic factors for measurement, and outcome measures. About 90% of studies were suggested to have a low risk of bias for study attrition and statistical analysis and presentation, but a 50% low risk of bias for confounding factors. However, the overall results for the risk of bias were considered to have a low risk of bias (supplement Figure s1B [Extended Data]44).
DMA
DMA was performed by pooling the effects of RCTs(N=15)14,17–20,25–30,33–36 between HBOT vs. control on healing rate with pooled RRs of 1.67 (95%CI:1.10, 2.52), (see supplement Figure s2A [Extended Data]44). Among the cohort studies, the pooled odds ratios (ORs) were 1.60 (95%CI: 0.84, 3.05). Considering hemoglobin spray vs. control of 4 cohort studies,12,15,22,23 the pooled OR was 1.92 (95%CI: 1.35, 2.73], but only one RCT did not estimate the pooled RRs from the analyses.
For subgroup analyses of the type of wound, the pooled effect size among hyperbaric vs control 1.69 (95%CI: 1.07, 2.68) of diabetes mellitus foot ulcer in RCTs(N=12),14,17–19,26–30,33,34,36 as well as in cohort studies(N=4)21,24,31,32 with pooled ORs of 1.60 (95%CI: 0.84, 3.05), but the number of studies in both venous ulcer and chronic ulcer was not sufficient to estimate the pooled effect size. Among hemoglobin spray vs. control, the number of included studies was insufficient for DMA.
NMA
NMA was performed using data from 16 RCTs14,16–20,25–30,33–36 with 900 patients, see Figure 2A). The treatment comparisons were pooled, indicating that hemoglobin spray and hyperbaric seemed to be better than the control with pooled RRs of 2.36 (95%CI: 0.74, 7.53) and 1.62 (95%CI: 1.02, 2.57), respectively, although these were not significant (Table 2). The probability of being the best treatment was hemoglobin spray, followed by hyperbaric treatment with SUCRAs of 67.9, and 32.1, respectively (Table 2). The adjusted funnel plot showed minimal asymmetry (Figure 3A).
Figure 2. Network of eligible treatment comparison mapping by study design.
Table 2. Mixed treatment comparisons for RCTs.
| Interventions | Control | Granulox | HBOT |
|---|---|---|---|
| Control | [0; 0] | 2.36 (0.74,7.53) | 1.62 (1.02,2.57) |
| Granulox | 0.42 (0.13,1.36) | [0.8; 67.9] | 0.69 (0.20,2.40) |
| HBOT | 0.62 (0.39,0.98) | 1.46 (0.42,5.09) | [0.7; 32.1] |
Figure 3. Adjusted funnel plot.
Eight cohort studies12,15,21–24,31,32 with 6,833 patients were included (Figure 2B). The trend of hemoglobin spray and hyperbaric suggested pooled RRs of 2.01 (95%CI: 1.21, 3.34) and 1.55 (95%CI: 0.84, 2.84), respectively compared with control, see Table 3. The probability indicated that hemoglobin spray was the best treatment, control, and hyperbaric with SUCRAs of 74.0, 25.9, and 0.1, respectively (Table 3). The adjusted funnel plot showed little asymmetry (Figure 3B).
Table 3. Mixed treatment comparisons for cohort.
| Interventions | Control | Granulox | HBOT |
|---|---|---|---|
| Control | [0; 0] | 2.01 (1.21,3.34) | 1.55 (0.84,2.84) |
| Granulox | 0.50 (0.30,0.83) | [0.9; 74.0] | 0.77 (0.36,1.67) |
| HBOT | 0.65 (0.35,1.19) | 1.30 (0.60,2.81) | [0.6; 25.9] |
Sensitivity analyses were performed considering the type of wound, which were 66.7%, 16.7%, and 16.7% for diabetes mellitus, foot ulcers, venous ulcers, and chronic ulcers, respectively. Considering the RCTs,13,15–19,24–29,32–35 only venous ulcer performed the analyses and also indicated that hemoglobin spray and hyperbaric were better than the control group, with pooled RRs of 2.36 (95%CI: 1.10, 5.07), and 1.21 (95%CI: 0.17, 8.80), respectively.
Among eight cohort studies,12,15,21–24,31,32 four cohort23,24,31,32 studies on diabetes mellitus foot ulcer suggested that hyperbaric and hemoglobin sprays seem to be better than the control of 1.65 (95%CI: 0.51, 5.36), and 1.32 (95%CI: 0.29, 6.12), respectively. In addition, chronic ulcer was considered in three cohort studies12,21,22 showing the same direction of hyperbaric and hemoglobin spray as the diabetes mellitus foot ulcer of (2.03 (95%CI: 0.89, 4.62), 1.84 (95%CI: 1.18, 2.86), respectively, compared with the control. However, the sensitivity analyses of the diabetes mellitus foot ulcer, chronic ulcer in RCTs, and venous ulcer in cohort studies were not estimated because the study was insufficient.
Discussion
We conducted a systematic review with network meta-analyses to compare important outcome i.e. rate of wound healing between topical hemoglobin therapy (hemoglobin spray) and HBOT. We identified a significant beneficial effect of hemoglobin spray as adjunct therapy compared with HBOT in improving the healing rate of chronic wounds. Our result showed that proportion of wound healing was 2.36 and 1.62 better than control in hemoglobin spray and HBOT, respectively. The proportion of wound healing with the hemoglobin spray was 1.32 times higher treatment success than that with HBOT. A network meta-analysis demonstrated that hemoglobin spray had the highest chance of treatment success (67.9%, SUCRA = 0.8) when compared with HBOT (treatment success was 32.1%, SUCRA = 0.7).
Even a small amount of clinical data regarding the effectiveness of hemoglobin spray as adjunctive therapy in chronic wounds demonstrated that it was effective in promoting wound healing, reducing inflammation, exudate, and slough.23 A recent meta-analysis found statistically significant benefits in achieving substantial healing across wound types.37 Several clinical studies have shown that HBOT is an effective therapy for patients with chronic wounds.38 It significantly reduces the risk of major amputation and improves the chance of healing diabetic foot ulcers.39 However, previous clinical trials on the effectiveness of HBOT have shown conflicting evidence regarding its efficacy in the treatment of chronic wounds.7,34,40 Data from the Crochrane review showed that HBOT can increased the rates of ulcers healing in the short term but not for long term results, and the variation of the study design and reporting of included trials, which means that we are not confident in the results.9
Our study had some strengths. To the best of our knowledge, this is the first network meta-analysis to compare the rate of wound healing between hemoglobin spray and HBOT. The benefits observed in this review can be elaborated in the real-world treatment of chronic wounds with hemoglobin spray. However, a few limitations could be avoided, that is, the small size and number of RCTs and nonrandomized studies that were available for inclusion. Clinical and practical implications suggest that clinicians and policy makers should support the hemoglobin spray prescription for the patients, in line with the consensus guidelines published previously. Hemoglobin spraying should always be used as the standard wound care, regular wound monitoring, and debridement.
Conclusion
Our evidence suggests that the proportion of wound healing in hemoglobin spray and HBOT groups was higher than that in the control group. A network meta-analysis demonstrated that hemoglobin spray had the highest chance of treatment success. There is a need for further studies using well-designed RCTs and updated meta-analyses to provide enough evidence to compare the effectiveness of hemoglobin spray and HBOT in clinical practice.
Download
Export To
metrics
| Views | Downloads | |
|---|---|---|
| F1000Research | - | - |
|
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Citations
CITE
how to cite this article
Wilasrusmee C, Supsamutchai C, Pornwaragorn C et al. The efficacy of hemoglobin spray in wound management: a systematic review and network meta-analysis of comparative studies [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:1265 (https://doi.org/10.12688/f1000research.148208.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.
Open Peer Review
Current Reviewer Status:
AWAITING PEER REVIEW
AWAITING PEER REVIEW
Key to Reviewer Statuses
VIEW
HIDE
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Comments on this article Comments (0)