Systematic review of clinical outcome reporting in randomised controlled trials of burn care.

INTRODUCTION: Systematic reviews collate trial data to provide evidence to support clinical decision-making. For effective synthesis, there must be consistency in outcome reporting. There is no agreed set of outcomes for reporting the effect of burn care interventions. Issues with outcome reporting have been identified, although not systematically investigated. This study gathers empirical evidence on any variation in outcome reporting and assesses the need for a core outcome set for burn care research.
METHODS: Electronic searches of four search engines were undertaken from January 2012 to December 2016 for randomised controlled trials (RCTs), using medical subject headings and free text terms including 'burn', 'scald' 'thermal injury' and 'RCT'. Two authors independently screened papers, extracted outcomes verbatim and recorded the timing of outcome measurement. Duplicate outcomes (exact wording ± different spelling), similar outcomes (albumin in blood, serum albumin) and identical outcomes measured at different times were removed. Variation in outcome reporting was determined by assessing the number of unique outcomes reported across all included trials. Outcomes were classified into domains. Bias was reduced using five researchers and a patient working independently and together.
RESULTS: 147 trials were included, of which 127 (86.4%) were RCTs, 13 (8.8%) pilot studies and 7 (4.8%) RCT protocols. 1494 verbatim clinical outcomes were reported; 955 were unique. 76.8% of outcomes were measured within 6 months of injury. Commonly reported outcomes were defined differently. Numbers of unique outcomes per trial varied from one to 37 (median 9; IQR 5,13). No single outcome was reported across all studies demonstrating inconsistency of reporting. Outcomes were classified into 54 domains. Numbers of outcomes per domain ranged from 1 to 166 (median 11; IQR 3,24).
CONCLUSIONS: This review has demonstrated heterogeneity in outcome reporting in burn care research which will hinder amalgamation of study data. We recommend the development of a Core Outcome Set. PROSPERO REGISTRATION NUMBER: CRD42017060908. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

This review is a comprehensive and systematic search for all clinical outcomes reported in randomised controlled trials of burn care between and including 2012 and 2016.

There is a detailed analysis of all reported outcomes and timing of outcome assessment.

A multidisciplinary team including a patient were involved in the study.

Quality assessment of studies was not undertaken as the purpose of the review was to extract clinical outcomes alone and not to assess the effect of an intervention.

Introduction

Each year an estimated 2–300 000 people die from burn injuries globally.1 Millions more suffer from burn-related disabilities and disfigurements.2 These injuries have functional, psychological, social and economic effects on survivors and their families. There are multiple strategies for managing burn wounds and the associated impact on patient physiology, with new care pathways and technology being introduced on a regular basis.3–5 The choice of treatment should be made using up-to-date, high quality scientific evidence.6 7 Systematic reviews of randomised controlled trials (RCT) are regarded as the highest quality evidence.8–10 Despite increasing numbers of published RCTs in burn care, systematic reviews have not provided evidence to support many commonly used interventions or management strategies.11–13

A well-designed RCT requires that outcomes are prespecified. Evidence synthesis requires that these outcomes are consistent across RCTs in the same healthcare area.14 In the context of clinical trials, Williamson et al in the Core Outcome Measures in Effectiveness Trials (COMET) handbook, define an outcome as ‘a measurement or observation used to capture and assess the effect of treatment such as assessment of side effects (risk) or effectiveness (benefits)’.15 Chan adds a temporal element: ‘a variable measured at a specific time point to assess the efficacy or harm of an intervention’.16 If RCTs report outcomes that cannot be collated due to differences in choice, definition or timepoint of assessment, evidence synthesis will not be effective or efficient. There is no agreed minimum set of outcomes important to patients and professionals for reporting in burn care trials and problems with outcome reporting in burn care research have previously been suggested.17–19

Prespecifying outcomes requires research to determine and agree the most important outcomes for a clinical condition. If this is not undertaken, the outcomes reported may not reflect patients’ or other stakeholders’ needs, outcomes will vary between studies (outcome reporting heterogeneity), and it will be difficult to determine if authors have reported all the outcomes they measured (outcome reporting bias).20 21 Choosing the most important outcomes to measure in burn care is complex, as patients are a heterogeneous population, with variations in age, mechanism of injury, depth, site and size of burn.22 23 The time frame at which outcomes are measured may also determine the types of outcomes assessed. Outcomes reported in clinical trials during the acute treatment phase include healing time, skin-graft loss, infection rates and National Health Service costs.24–27 Longer-term reported outcomes relate to functional, cosmetic and psychological issues.28

To date, there has been no formal investigation into outcome reporting in trials of burn care. The purpose of this study is to examine clinical outcome reporting in burn care research, to consider the types, definitions and timing of outcomes measured and to consider the need for a Core Outcome Set (COS) in this field.

Methods

This review is focused on clinical, observer-reported outcomes in RCTs assessing the impact of interventions in burn care. It adhered to a prespecified protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.29

Study eligibility

Studies were included if they met the following:

Types of studies: We included full text RCTs along with RCT protocols and pilot studies. The study design was limited to RCTs, as any final COS will be used for RCT reporting.29 We excluded protocols and pilot studies if the full RCT had been published within the selected time period. We also excluded conference proceedings and abstracts, non-English language publications and studies not involving human subjects.

Types of participants: We included studies recording outcomes from patients of any age with a cutaneous burn of any type or size, determined by either clinician evaluation or objective assessment, or both, which required treatment in any healthcare facility. Studies where the population consisted of patients with combined thermal and mechanical injuries were only included if it was possible to separate out the burn care outcomes. Trials studying patients with pure carbon monoxide poisoning, chemical ocular or caustic oesophageal burns were excluded, as the former does not involve a burn and the latter have different aetiology and management to cutaneous burns.

Type of interventions: Any surgical or non-surgical burn care intervention with any appropriate comparator.

Types of outcomes: Defined as the exact terms used in a published trial abstract, methods or results including tables and figures for any observer-reported clinical endpoint. These included physiological, metabolic or adverse or mortality events measured by researchers and relevant to patients’ recovery and long-term well-being after burn care.30 Trials assessing quality of life were only included if the data were observer-reported.

Identification of studies

Electronic searches of Ovid MEDLINE, Ovid EMBASE, Web of Science and The Cochrane Library were searched from 1 January 2012 to 31 December 2016 for RCTs related to burn care using medical subject heading and free text terms including ‘burn’, ‘scald’ ‘thermal injury’ and ‘RCT’. This period was chosen so that the outcomes extracted, reflected use in trials relating to modern burn care. Limiting the review to 5 years allowed us to balance workload against the likelihood of selecting enough trials fulfilling inclusion criteria to demonstrate whether heterogeneity of outcome reporting was present in burn care research. The thesaurus vocabulary of each database was used to adapt the search terms. The search strategy for Ovid MEDLINE is included in a previous publication and in online supplementary appendix A.29

Study selection process

Prior to both abstract and full-text screening, all review authors underwent training to ensure a comparable understanding of the purpose of the review and the eligibility criteria. The reference management software EndNote V.6 (Clarivate Analytics, Boston; available at http://endnote.com/) was used to compile all titles derived from the initial searches, with duplicates removed for the review authors to screen titles and abstracts against the eligibility criteria. Screening of titles and abstracts was completed independently, then in duplicate by two authors (AY, AD) with experience in systematic review methodology. All screening disagreements were discussed, with any outstanding disagreements resolved by an independent reviewer (JB). Any studies appearing to meet the inclusion criteria based on the abstract were retrieved as full-text articles. Two reviewers then read the full-text articles in their entirety to assess for eligibility, with decisions on inclusion and exclusion recorded (figure 1 for flow diagram). Reasons for exclusion were ordered hierarchically (box 1) and applied to each full text. The highest reason for exclusion met by a paper was recorded as its reason for exclusion. Any disagreements were discussed with another author (JB).

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. PRO, patient reported outcome; RCT, randomised controlled trial.

Duplicate.

Not published between 1 January 2012 and 31 December 2016.

Not written in English.

Not relating to burns or burn care alone.

Population is non-human subjects (eg, animal studies, modelling).

Abstract with no full text given.

Study is not a randomised controlled trial testing an intervention on burn care.

Laboratory based, not carried out in clinical setting, for example, exudate or blood samples from humans tested within laboratory.

Systematic review paper, commentary paper.

Reports only patient-reported outcomes.

Volunteer study.

Oesophageal burns.

Ocular burns.

Anaesthetic/sedation technique.

Diagnostic test trial.

Unavailable anywhere.

Follow-up studies.

Quality assessment

The aim of this study was to comprehensively document any variation in clinical outcomes selected, defined, measured and reported in burn care RCTs and not to synthesise data about the effect of interventions. Inclusion of all trials was necessary to demonstrate if a variation in outcome reporting was present across trials, regardless of quality of methodology of the trial. We therefore decided not to undertake a quality assessment of studies because it was not relevant to the data being recorded in this review; simply the nature and description of the unique outcomes reported in each study.

Data extraction

Data were extracted into a standardised data extraction sheet (Microsoft Excel). This included study author, country or countries recruiting (categorised into the United Nations six regions31), publication year, number of sites and number of participants recruited per trial, design (full RCT, pilot, protocol) and intervention tested. For protocols, the planned participant inclusion criteria and sample size were extracted.

No distinction was made between primary or secondary outcomes, although this was noted and is part of a separate project. All outcomes were extracted verbatim, with 20% of the extracted data verified by a second reviewer. True duplicates, spelled and worded the same, were deleted. As a second process, two reviewers (a clinician and researcher) discussed all verbatim outcomes to assess duplicates in meaning but spelled or worded in a slightly different manner; such as length of time in hospital and number of days in hospital, platelet level and levels, and serum interleukin (IL) 10 and IL-10 in blood. These were named as one outcome with wording chosen by the reviewers and the others deleted as duplicates. The remaining outcomes were therefore all different in meaning. Any discrepancies were discussed with a senior researcher (JB). The number of outcomes per trial and the variation of outcomes between trials was recorded.

The time after injury that outcomes were measured were noted separately in order to (a) assess the heterogeneity in outcome measurement timing and (b) to understand at what stage after injury the effects of the intervention were being assessed. If a single outcome was assessed at different timepoints, all assessment timings were recorded. Data extraction for the timing of outcome reporting from 10% of trials was undertaken independently by another researcher. Timings of outcome assessment were categorised into time periods; <1 month, >1 month and <3 months, >3 months and <6 months after injury, >6 months and <1 year and >1 year and <3 years, and >3 years. We reported two other outcome time periods; those assessed during acute hospitalisation and during burn wound healing, as these were commonly reported in the literature with no proscribed timepoint. However, it was clear from the reported length of stay and healing data, that all these outcomes were assessed within 6 months of injury. The frequency of outcomes reported within each time period was recorded.

The data were tabulated so that each study was listed with study and population details along with outcomes measured. Outcomes were extracted from this spreadsheet into another, with duplicates removed as described above. Outcomes measuring the same healthcare issue but at different timepoints were noted as one outcome for the final set. These final unique outcomes were then grouped into domains.

Classification of outcomes into domains

Outcome domains are groups of similar outcomes. This organisation is necessary, as maintaining a large set of outcomes when a significant number are similar, would make any future classification of the outcomes in terms of importance, extremely challenging.

Outcomes were classified into domains in a three-stage iterative approach. In stage 1, four researchers (a clinically trained burn care researcher, a burn research associate and two senior research nurses experienced in burn care) independently reviewed the list of outcomes and attributed a potential domain to each one using their own terms. In stage 2, the researchers met to review the domains and agreed (1) appropriate groupings of outcomes into domains and (2) an appropriate name for each domain. Rules for attribution of outcomes to domains were recorded in a coding log to ensure consistency. In stage 3, a patient representative reviewed the outcomes and their attributed domains to check for clarity of domain name, and that the outcomes under each domain were appropriately attributed. A final meeting with an experienced outcome researcher was held to finalise outcomes and domains. The use of a published classification system was not undertaken as none appeared to allow the flexibility or fit to the types of outcomes reported in burn care trials.32 33

The results described below indicate the characteristics of the reported studies and provide detail on heterogeneity of outcome reporting between studies, outcome definitions, timepoints and outcome domains.

Patient involvement

The need for a burn care COS project was conceived following discussions regarding clinical healthcare Key Performance Indicators with professionals and patients. The patients were vocal about outcomes important to them which they felt were overlooked by professionals, such as pain. The systematic review was discussed at regular project steering group meetings attended by three patients with burns and one parent of a child with burns. A patient with burns is a coauthor and was involved with writing and editing of this article as well as with the naming of the outcome domains. Dissemination will be to the lay representatives of the steering group and will inform the Core Outcome Set study in which patients are actively involved.

Results

Included studies and study protocols

The initial search strategy identified 3110 studies. Following de-duplication, a total of 2070 studies remained. Independent scrutiny of the titles and abstracts identified 306 potentially relevant articles for full text review. Of these, 158 studies did not meet our inclusion criteria and were excluded (PRISMA flow diagram; figure 1). Therefore, a total of 147 studies formed the basis of this study.24 34–178

Studies

Of the 147 studies (table 1), 86.4% (127) were reports of full RCTs, 8.8% (13) were pilot studies and 4.8% (7) were study protocols. The number of studies published increased between 2012 and 2016, with 26 RCTs published in 2012 and 40 in 2016 (table 2).

Table 1

Included randomised controlled trials

Trial title	First author	Year of publication
1. Comparison of silver nylon wound dressing and silver sulfadiazine in partial burn wound therapy.34	Abedini	2012
2. Healing of burn wounds by topical treatment: A randomized controlled comparison between silver sulfadiazine and nano-crystalline silver.35	Adhya	2015
3. An analysis of deep vein thrombosis in burn patients (Part 1): Comparison of D-dimer and Doppler ultrasound as screening tools.36	Ahuja	2016
4. An analysis of deep vein thrombosis in burn patients (part II): A randomized and controlled study of thrombo-prophylaxis with low molecular weight heparin.37	Ahuja	2016
5. A four arm, double blind, randomized and placebo-controlled study of pregabalin in the management of post-burn pruritus.38	Ahuja	2012
6. Propranolol attenuates haemorrhage and accelerates wound healing in severely burned adults.39	Ali	2015
7. Aerobic exercise training in modulation of aerobic physical fitness and balance of burned patients.40	Ali	2015
8. Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds.41	Aramwit	2013
9. A Randomized Controlled Trial Comparing Endoscopic-Assisted Versus Open Neck Tissue Expander Placement in Reconstruction of Post-Burn Facial Scar Deformities.42	As’adi	2016
10. A prospective, randomised study of a novel transforming methacrylate dressing compared with a silver-containing sodium carboxymethylcellulose dressing on partial-thickness skin graft donor sites in burn patients.43	Assadian	2015
11. Multimodal quantitative analysis of early pulsed-dye laser treatment of scars at a pediatric burn hospital.44	Bailey	2012
12. Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: a randomized, controlled, double-blind clinical trial.45	Bechir	2013
13. A prospective randomized trial comparing silver sulfadiazine cream with a water-soluble poly-antimicrobial gel in partial-thickness burn wounds.46	Black	2015
14. Clinical effectiveness of dermal substitution in burns by topical negative pressure: a multicenter randomized controlled trial.47	Bloeman	2012
15. Effect of subcutaneous epinephrine/saline/local anesthetic versus saline-only injection on split-thickness skin graft donor site perfusion, healing, and pain.48	Blome Eberwein	2013
16. A randomized controlled study of silver-based burns dressing in a pediatric emergency department.49	Brown	2016
17. Cost-Effectiveness of a Nonpharmacological Intervention in Pediatric Burn Care.50	Brown	2015
18. Play and heal: randomized controlled trial of DittoTM intervention efficacy on improving re-epithelialization in pediatric burns.51	Brown	2013
19. The implementation and evaluation of therapeutic touch in burn patients: an instructive experience of conducting a scientific study within a non-academic nursing setting.	Busch	2012
20. Prophylactic sequential bronchoscopy after inhalation injury: results from a 3 year prospective randomized trial.52	Carr	2013
21. Burns injury in children: is antibiotic prophylaxis recommended?53	Chahed	2014
22. A randomized controlled trial to compare the effects of liquid versus powdered recombinant human growth hormone in treating patients with severe burns.54	Chen	2016
23. The Effect of Continuous Sedation Therapy on Immunomodulation, Plasma Levels of Antioxidants, and Indicators of Tissue Repair in Post-Burn Sepsis Patients.55	Chen	2015
24. Application of acellular dermal xenografts in full-thickness skin burns.56	Chen	2013
25. Effectiveness of medical hypnosis for pain reduction and faster wound healing in pediatric acute burn injury: study protocol for a randomized controlled trial.57	Chester	2016
26. Safety of recombinant human granulocyte-macrophage colony-stimulating factor in healing paediatric severe burns.58	Chi	2015
27. Comparison of three cooling methods for burn patients: A randomized clinical trial.59	Cho	2016
28. The effect of burn rehabilitation massage therapy on hypertrophic scar after burn: a randomized controlled trial.60	Cho	2014
29. Effect of extracorporeal shock wave therapy on scar pain in burn patients: A prospective, randomized, single-blind, placebo-controlled study.61	Cho	2016
30. Characterization of early thermal burns and the effects of hyperbaric oxygen treatment: a pilot study.62	Chong	2013
31. Effects of different duration exercise programs in children with severe burns.63	Clayton	2016
32. The effect of healing touch on sleep patterns of pediatric burn patients.64	Cone	2014
33. Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn.65	Csontos	2012
34. The effects of intravenous glutamine supplementation in severely burned, multiple traumatized patients.66	Cucerean-Badica	2013
35. A comparison between occlusive and exposure dressing in the management of burn wound.	Dallal	2016
36. Evaluation of the ‘Early’ Use of Albumin in Children with Extensive Burns: A Randomized Controlled Trial.	Dittrich	2016
37. Interim pressure garment therapy (4–6 mmHg) and its effect on donor site healing in burn patients: study protocol for a randomised controlled trial.67	Donovan	2016
38. Effect of whole body vibration on leg muscle strength after healed burns: a randomized controlled trial.68	Ebid	2012
39. Effect of isokinetic training on muscle strength, size and gait after healed pediatric burn: a randomized controlled study.69	Ebid	2014
40. Effect of 12 week isokinetic training on muscle strength in adult with healed thermal burn.70	Ebid	2012
41. Effects of whole-body vibration exercise on bone mineral content and density in thermally injured children.71	Edionwe	2016
42. Efficacy of platelet rich plasma application in comparison to conventional dressing therapy in partial thickness burn wound.72	Ehmer al Ibran	2014
43. Effect of probiotic administration in the therapy of pediatric thermal burn.73	El-ghazely	2016
44. Heparin/N-acetylcysteine: an adjuvant in the management of burn inhalation injury: a study of different doses.74	Elsharnouby	2014
45. The effect of levamisole on mortality rate among patients with severe burn injuries.75	Fatemi	2013
46. Impact of stress-induced diabetes on outcomes in severely burned children.76	Finnerty	2014
47. Outcome of Burns Treated With Autologous Cultured Proliferating Epidermal Cells: A Prospective Randomized Multi-center Intra-patient Comparative Trial.77	Gardien	2016
48. Randomized controlled trial of three burns dressings for partial thickness burns in children.78	Gee Kee	2015
49. Topical petrolatum gel alone versus topical silver sulfadiazine with standard gauze dressings for the treatment of superficial partial thickness burns in adults: a randomized controlled trial.79	Genuino	2014
50. HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial.80	Glas	2014
51. A multi-center study on the regenerative effects of erythropoietin in burn and scalding injuries: study protocol for a randomized controlled trial.82	Gunter	2013
52. Early rehabilitative exercise training in the recovery from pediatric burn.83	Hardee	2014
53. Quality of pediatric second-degree burn wound scars following the application of basic fibroblast growth factor: results of a randomized, controlled pilot study.84	Hayashida	2012
54. Long-term propranolol use in severely burned pediatric patients: a randomized controlled study.85	Herndon	2012
55. Reversal of growth arrest with the combined administration of oxandrolone and propranolol in severely burned children.86	Herndon	2016
56. Cost-Effectiveness of Laser Doppler Imaging in Burn Care in The Netherlands: A Randomized Controlled Trial.87	Hop	2016
57. Effect of music intervention on burn patients’ pain and anxiety during dressing changes.88	Hsu	2016
58. Low dose of glucocorticoid decreases the incidence of complications in severely burned patients by attenuating systemic inflammation.89	Huang	2015
59. An assessment of early Child Life Therapy pain and anxiety management: A prospective randomised controlled trial.90	Hyland	2015
60. Prospective, randomised controlled trial comparing VersajetTM hydrosurgery and conventional debridement of partial thickness paediatric burns.91	Hyland	2015
61. Construction of skin graft seams in burn patients: A prospective randomized double-blinded study.92	Isaac	2016
62. Multi-axis shoulder abduction splint in acute burn rehabilitation: a randomized controlled pilot trial.93	Jang	2015
63. Glucose control in severely burned patients using metformin: An interim safety and efficacy analysis of a phase II randomized controlled trial.94	Jeschke	2016
64. The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes.95	Jeschke	2012
65. The Effect of Distraction Technique on the Pain of Dressing Change among 3–6 Year-old Children.96	Kaheni	2016
66. Prospective randomize-controlled comparison between silicone plus herbal extract gel versus Aloe Vera gel for burn scar prophylaxis.97	Keorochana	2015
67. Effects of Enteral Glutamine Supplementation on Reduction of Infection in Adult Patients with Severe Burns.98	Kibor	2014
68. Effects of sustained release growth hormone treatment during the rehabilitation of adult severe burn survivors.99	Kim	2016
69. Virtual reality for acute pain reduction in adolescents undergoing burn wound care: a prospective randomized controlled trial.100	Kipping	2012
70. The effects of splinting on shoulder function in adult burns.101	Kolmus	2012
71. Prospective study on burns treated with Integra, a cellulose sponge and split thickness skin graft: comparative clinical and histological study--randomized controlled trial.102	Lagus	2013
72. Evaluation of an oxygen-diffusion dressing for accelerated healing of donor-site wounds.103	Lairet	2014
73. Anti-inflammatory effect of taurine in burned patients.104	Lak	2015
74. A randomized controlled pilot study comparing aqueous cream with a beeswax and herbal oil cream in the provision of relief from postburn pruritus.105	Lewis	2012
75. Human acellular dermal matrix allograft: A randomized, controlled human trial for the long-term evaluation of patients with extensive burns.106	Li	2015
76. Selective digestive decontamination attenuates organ dysfunction in critically ill burn patients.107	Lopez-Rodriguez	2015
77. Results of a prospective randomized controlled trial of early ambulation for patients with lower extremity autografts.108	Lorello	2014
78. Moist occlusive dressing (Aquacel(Â) Ag) versus moist open dressing (MEBO(Â)) in the management of partial-thickness facial burns: a comparative study in Ain Shams University.109	Mabrouk	2012
79. Enhancement of burn wounds healing by platelet dressing.110	Maghsoudi	2013
80. Effect of immune-enhancing diets on the outcomes of patients after major burns.111	Mahmoud	2014
81. Silver-coated nylon dressing plus active DC microcurrent for healing of autogenous skin donor sites.112	Malin	2013
82. The application of platelet-rich plasma in the treatment of deep dermal burns: A randomized, double-blind, intra-patient-controlled study.113	Marck	2016
83. Clinical safety and efficacy of probiotic administration following burn injury.114	Mayes	2015
84. Three donor site dressings in pediatric split-thickness skin grafts: study protocol for a randomised controlled trial.115	McBride	2015
85. Evaluation of who oral rehydration solution (ORS) and salt tablets in resuscitating adult patients with burns covering more than 15% of total body surface area (TBSA).116	Moghazy	2016
86. Efficacy and adverse events of early high-frequency oscillatory ventilation in adult burn patients with acute respiratory distress syndrome.117	Mohamed	2016
87. Effect of amniotic membrane on graft take in extremity burns.118	Mohammadi	2013
88. Comparison of the application of allogeneic fibroblast and autologous mesh grafting with conventional method in the treatment of third-degree burns.119	Moravvej	2016
89. Effect of low-intensity laser on the neuropathic common peroneal nerve post burn.120	Mowafy	2016
90. Clinical Efficacy Test of Polyester Containing Herbal Extract Dressings in Burn Wound Healing.121	Muangman	2016
91. Effect of oral olive oil on healing of 10%–20% total body surface area burn wounds in hospitalized patients.123	Najmi	2015
92. Double-blind, randomized, pilot study assessing the resolution of postburn pruritus.124	Nedelec	2012
93. Comparing outcomes of sheet grafting with 1:1 mesh grafting in patients with thermal burns: a randomized trial.125	Nikkah	2014
94. Comparison of hydrogel produced by radiation as applied at the research center (Yazd branch) with maxgel and routine dressing for second-degree burn repair in Yazd burn hospital.126	Noorbala	2016
95. Effectiveness of cerium nitrate-silver sulfadiazine in the treatment of facial burns: a multi-center, randomized, controlled trial.127	Oen	2012
96. Influences of purposeful activity versus rote exercise on improving pain and hand function in pediatric burn.128	Omar	2012
97. Botulinum toxin and burn induces contracture.130	Omranifard	2016
98. Results of a pilot multi-center genotype-based randomized placebo-controlled trial of propranolol to reduce pain after major thermal burn injury.129	Orrey	2015
99. A proper enteral nutrition support improves sequential organ failure score and decreases length of stay in hospital in burned patients.131	Ostradrahimi	2016
100. Topical silver sulfadiazine vs collagenase ointment for the treatment of partial thickness burns in children: a prospective randomized trial.132	Ostlie	2012
101. Prospective randomized phase II Trial of accelerated re-epithelialization of superficial second-degree burn wounds using extracorporeal shock wave therapy.133	Ottomann	2012
102. A randomized and controlled multi-center prospective study of the Chinese medicinal compound Fufang Xuelian Burn Ointment for the treatment of superficial and deep second-degree burn wounds.134	Ouyang	2014
103. Prospective comparison of packed red blood cell-to-fresh frozen plasma transfusion ratio of 4: 1 vs 1: 1 during acute massive burn excision.135	Palmieri	2012
104. A herbal cream consisting of Aloe Vera, Lavandulastoechas, and Pelargonium roseum as an alternative for silver sulfadiazine in burn management.136	Panahi	2012
105. Interactive gaming consoles reduced pain during acute minor burn rehabilitation: A randomized, pilot trial.137	Parker	2016
106. A Pilot Prospective Randomized Control Trial Comparing Exercises Using Videogame Therapy to Standard Physical Therapy: 6 Months Follow-Up.138	Parry	2015
107. An open, prospective, randomized pilot investigation evaluating pain with the use of a soft silicone wound contact layer vs bridal veil and staples on split thickness skin grafts as a primary dressing.139	Patton	2013
108. Effects of community-based exercise in children with severe burns: A randomized trial.140	Pena	2015
109. Effects of propranolol and exercise training in children with severe burns.141	Porro	2013
110. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy.142	Porro	2012
111. Clinical effectiveness, quality of life and cost-effectiveness of Flaminal versus Flamazine in the treatment of partial thickness burns: study protocol for a randomized controlled trial.144	Rashaan	2016
112. Five-Year Outcomes after Long-Term Oxandrolone Administration in Severely Burned Children: A Randomized Clinical Trial.145	Reeves	2016
113. A novel rapid and selective enzymatic debridement agent for burn wound management: a multi-center RCT.146	Rosenburg	2013
114. Effects of cholecalciferol supplementation and optimized calcium intakes on vitamin D status, muscle strength and bone health: a 1 year pilot randomized controlled trial in adults with severe burns.147	Rousseau	2015
115. Evaluation of Amniotic Membrane Effectiveness in Skin Graft Donor Site Dressing in Burn Patients.148	Salehi	2015
116. A feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury.143	Santos Portilla	2013
117. Perioperative treatment algorithm for bleeding burn patients reduces allogeneic blood product requirements.149	Schaden	2012
118. A prospective clinical trial comparing Biobrane, Dressilk, and PolyMem dressings on partial-thickness skin graft donor sites.150	Schulz	2016
119. Effectiveness of Aloe Vera gel compared with 1% silver sulphadiazine cream as burn wound dressing in second degree burns.151	Shahzad	2013
120. The comparison between modified kligman formulation versus kligman formulation and intense pulsed light in the treatment of the post-burn hyperpigmentation.152	Siadat	2016
121. A comparative study of spray keratinocytes and autologous meshed split-thickness skin graft in the treatment of acute burn injuries.154	Sood	2015
122. Long-Term Administration of Oxandrolone Improves Lung Function in Pediatric Burned Patients.155	Sousse	2016
123. An open, parallel, randomized, comparative, multicenter investigation evaluating the efficacy and tolerability of Mepilex Ag versus silver sulfadiazine in the treatment of deep partial-thickness burn injuries.156	Tang	2015
124. Non-ablative fractional laser provides long-term improvement of mature burn scars - A randomized controlled trial with histological assessment.157	Taudorf	2015
125. Fluid therapy lidco controlled trial - Optimization of volume resuscitation of extensively burned patients through noninvasive continuous real-time hemodynamic monitoring LiDCO.158	Tokarik	2013
126. Burn donor site dressing using melolin and flexigrid versus conventional dressing.159	Vejdan	2015
127. Laser Doppler imaging as a tool in the burn wound treatment protocol.160	Venclauskiene	2014
128. Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial.161	Venet	2015
129. A Comparative Study of Paediatric Thermal Burns Treated with Topical Heparin and Without Heparin.162	Venkatachalapathy	2014
130. Aquacel() Ag dressing versus ActicoatTM dressing in partial thickness burns: a prospective, randomized, controlled study in 100 patients. Part 1: burn wound healing.24	Verbelen	2014
131. Skin stretching for primary closure of acute burn wounds.163	Verhaegen	2014
132. Xbox KinectTM based rehabilitation as a feasible adjunct for minor upper limb burns rehabilitation: A pilot RCT.164	Voon	2016
133. Local application of low-dose insulin in improving wound healing after deep burn surgery.165	Wang	2016
134. Gabapentin is ineffective as an analgesic adjunct in the immediate postburn period.166	Wibbenmeyer	2014
135. A prospective randomised clinical pilot study to compare the effectiveness of Biobrane (R) synthetic wound dressing, with or without autologous cell suspension, to the local standard treatment regimen in paediatric scald injuries.167	Wood	2012
136. Effective symptomatic treatment for severe and intractable pruritus associated with severe burn-induced hypertrophic scars: A prospective, multicenter, controlled trial.168	Wu	2016
137. Propranolol reduces cardiac index but does not adversely affect peripheral perfusion in severely burned children.169	Wurzer	2016
138. A new method of microskin autografting with a Vaseline-based moisture dressing on granulation tissue.170	Xiao	2014
139. Recombinant human granulocyte-macrophage colony-stimulating factor hydrogel promotes healing of deep partial thickness burn wounds.171	Yan	2012
140. A comparative study of the dressings silver sulfadiazine and Aquacel Ag in the management of superficial partial-thickness burns.172	Yarboro	2013
141. A clinical trial designed to evaluate the safety and effectiveness of a thermosensitive hydrogel-type cultured epidermal allograft for deep second-degree burns.173	Yim	2014
142. Study of the use of recombinant human granulocyte-macrophage colony-stimulating factor hydrogel externally to treat residual wounds of extensive deep partial-thickness burn.174	Yuan	2015
143. Effect of Olea ointment and Acetate Mafenide on burn wounds - A randomized clinical trial.175	Zahmatkesh	2015
144. Effects of puerarin on the inflammatory role of burn-related procedural pain mediated by P2×7 receptors.176	Zhang	2013
145. Effects of early enteral nutrition on the gastrointestinal motility and intestinal mucosal barrier of patients with burn-induced invasive fungal infection.81	Zhang	2016
146. Maximizing the safety of glycerol preserved human amniotic membrane as a biological dressing.177	Zidan	2015
147. Therapeutic Value of Blood Purification and Prognostic Utilities of Early Serum Procalcitonin, C Reactive Protein, and Brain Natriuretic Peptide Levels in Severely Burned Patients with Sepsis.178	Zu	2015

Table 2

Randomised controlled tiral (RCT) detail

	Studies
Number of RCTs	127/147 (86.4)
Number of pilot studies	13/147 (8.8)
Number of RCT protocols	7/147 (4.8)
World region for recruitment
Asia	54/147 (36.7)
North America	36/147 (24.5)
Europe	26/147 (17.7)
Africa	15/147 (8.5)
Latin America	1/147 (0.7)
Australasia	15/147 (8.5)
Year published
2012	26/147 (17.8)
2013	24/147 (16.3)
2014	24/147 (16.3)
2015	33/147 (22.4)
2016	40/147 (27.2)
Number of sites
1	132/147 (89.8)
2–3	9/147 (6.1)
4–5	2/147 (1.4)
>5	4/147 (2.7)
Number of participants in full RCTs
<10	4/127 (3.1)
11–50	62/127 (48.8)
51–100	39/127 (30.7)
101–150	11/127 (8.7)
>150	11/127 (8.7)
Participants recruited
<18 years	24/147 (16.3)
>18 years	59/147 (40.1)
Mixed age range	25/147 (17.0)
Not stated	34/147 (23.1)
N/A (protocol)‡	5/147 (3.4)
Type of intervention
Dressings and wound care	38/147 (25.9)
Surgical technique	19/147 (12.9)
Treatment of pain or itch*	16/147 (10.9)
Impact of exercise and rehabilitation	13/147 (8.8)
Intensive care management	10/147 (6.8)
Treatment of hypermetabolism	8/147 (5.4)
Nutrition	8/147 (5.4)
Scar management	7/147 (4.8)
Treatment of inhalational injury	3/147 (2.0)
Use of topical rHGM	3/147 (2.0)
Use of rHGH	3/147 (2.0)
Sugar management	2/148 (2.0)
Treatment of infection	2/147 (1.4)
Treatment of DVT	2/147 (1.4)
Blood management	2/147 (1.4)
Extracorporeal shock wave therapy	2/147 (1.4)
Platelet-rich plasma use	2/147 (1.4)
Others†	7/147 (5.4)

*Inc. distraction for dressing changes.

†Inc. levamisole, hyperbaric oxygen, fibroblast growth factor, oral calcium use, ketoconazole, low intensity laser.

‡No participants reported as study is a protocol.

DVT, deep vein thrombosis; N/A, not applicable; rHGH, recombinant human growth hormone; rHGM, recombinant Human Granulocyte-Macrophage colony-stimulating factor.

A total of 9022 participants were recruited across the 140 studies (study protocols not included n=7). The number of patients recruited per trial ranged from 3 to 612 (median 50; IQR 30–88) for full RCTs and from 10 to 52 (median 21; IQR 16–28) for pilot studies. 50.4% of full RCTs recruited fewer than 50 participants (table 2). The majority (89.7%) of studies recruited (or planned to recruit) participants on one site alone. Of the 10.2% (15) of studies that were multicentre, nine (60%) undertook research at only two or three sites. Thirty-two countries from the six global regions recruited patients into the 147 RCTs (table 2). The country that undertook the most studies was the USA with 22.4% (33), followed by Iran with 12.9% (19) and China with 10.9% (16) of published studies. Of the 32 countries, 59.3% (19) published only one trial in this time period. The most common trial interventions related to dressings and wound care 29.2% (43), followed by surgical technique 11.6% (17) and management of pain and itch 10.9% (16) (table 2).

Outcomes

A total of 1494 clinical outcomes were reported of which, after de-duplication, 955 different, unique outcomes remained. Of the 1494 outcomes reported, 27.7% (421) were common across two studies or more. Of these outcomes, 50.3% (78) appear in only two trials and 84.5% appear in five trials or fewer. The number of outcomes reported per trial varied from one to 37 (median 9; IQR 5,13) (table 3). No single outcome was reported across all 147 studies.

Table 3

Reported outcomes

Number of outcomes per study
1	4/147 (27.2%)
2–5	34/147 (23.1%)
6–10	53/147 (36.1%)
11–20	41/147 (27.9%)
>20	15/147 (10.2%)

Outcome definition variation: Outcomes assessing the same healthcare issue were commonly defined differently. An example is burn wound healing which was defined in 166 different ways. Examples include: healing percentage at specified timepoints, incidence of complete wound healing, incidence of 30% wound healing and length of time until 50% epithelialisation of burn wound. Similar variation in definition of burn wound infection existed with 79 unique outcome definitions including: bacterial colonisation of burn wound, days of antibiotics, incidence of local infection, incidence of positive wound cultures, periwound redness, rate of bacterial clearance from wound and number of inflammatory cells in the wound.

Outcome timing variation: There were 2743 outcomes measured if the same outcome measured at different timepoints across all the 147 RCTs are included; for example, size of burn wound measured at 1 week and again at 2 weeks, were recorded as different outcomes for this exercise. Of these, 76.9% (2109) were assessed at less than 6 months after injury, 16.6% (456) were measured after 6 months and before 3 years after injury, and only 5.1% (140) were measured at more than 3 years after injury (figure 2). The timing of outcome measurement was not reported for 38 outcomes.

Figure 2

Reported timepoint at which outcome was assessed. mths, months; NS, not stated; yrs, years.

Outcome domains: The 955 different clinical outcomes were organised into 54 domains (groups of similar outcomes). Table 4 categorises the domains into over-arching categories and gives examples and total numbers of outcomes within each domain.

Table 4

Outcome category, domains and examples of outcomes

Outcome category	Outcome domain	Outcome examples	No of unique outcomes per domain
Patient-reported	Ability to carry out daily tasks	Functional level of independence	1
	Anxiety about medical procedures and appointments	Pain anxiety Anxiety before dressing changes	4
	Generalised anxiety	General anxiety	1
	Appearance	Facial symmetry Overall scar appearance	3
	Blister fluid	Amount of exudate	3
	Burden of care	Frequency of dressing changes Time taken for daily wound cleaning	7
	Comfort of dressings	Dressing comfort	1
	Psychological well-being	Improvement in well-being	1
	Mental ability		2
	Quality and quantity of sleep	Quantity of sleep Incidence of sleep disturbance	17
	Effect of scar on movement (contractures)	Cognitive performance	3
	Return to work/school or previous function	Return to work or previous function	1
	Burn wound pain	Wound pain intensity at baseline Pain tolerance	29
	Donor site pain	Donor site pain at rest Donor site pain while walking	6
	Pain during procedures	Wound pain at dressing changes Pain during hydrotherapy	14
	Scar pain	Functional scar pain Incidence of neuropathic pain	13
	Itch	Baseline pruritus Itch severity reduction	24
Pathophysiological	Ability to fight infection	Change in IgA IL-1beta in blood Serum interferon gamma levels	36
	Body weight maintenance	Incidence of weight loss Body weight decrease from baseline	26
	Bone strength	Bone mineral density Incidence of osteoporosis	30
	Breathing and lungs	Forced expiratory volume in 1 s Functional residual capacity	27
	Donor site problems after healing	Donor site pigmentation Sensation of donor site	24
	Effect of burn on genes	Gene expression patterns	1
	Effect of burn on how the body uses energy	Change in percentage of predicted resting energy expenditure	2
	Effect on heart and blood circulation	Incidence of cardiomegaly Number of patients requiring norepinephrine	28
	Fitness	Maximum aerobic capacity Exercise maximum minute ventilation	12
	Growth in children	Duration of growth arrest Percentage change in height	10
	How well muscles work	Facial mimic function Change in muscle function	9
	Mobility	Stride length Knee range of motion	22
	Kidney function	Incidence of acute kidney injury Requirement for renal replacement therapy	17
	Liver function	Hepatic function Ammonia levels	11
	Medical tests to indicate how unwell a patient is	Albumin level Change in pH	84
	More than one organ failing (multiorgan failure)	Incidence of multi organ failure Percentage of patients with organ dysfunction	7
	Muscle strength	Knee extensor strength Hamstring strength adjusted for body weight	30
	Stomach and bowel function	Days of diarrhoea Incidence of abdominal distension	13
	Burn wound healing	Burn wound area at timepoints Days until wound closure	166
	Donor site healing	Donor site healing to 90% Time to donor site re-epithelialisation	9
Complications	Complications of drug treatment	Adverse drug reactions Allergic dermatitis	52
	Blood product transfusion	Blood transfused per kg during hospitalisation Total volume FFP transfused	11
	Burn wound infection	Wound bacterial colonisation Wound contamination postoperatively	80
	Death from burn injury	Mortality related to burn size	1
	Death from any cause	Overall mortality In-hospital mortality	14
	Effects of fluid from a drip	Incidence of fluid creep Net fluid balance at specified times	17
	Infections other than burn wound infection	Incidence of central catheter related infections Pulmonary infection	7
	Sepsis	Days of sepsis Incidence of positive blood cultures	7
Scar-related	Scar colour	Erythema index Scar melanin levels	25
	Scar texture	Scar height Change in scar distensibility	47
	Scar size	Scar surface area	1
	Treatment for scars	Numbers of patients assessed for scar management Numbers of patients needing scar management	2
Healthcare-related	Costs of treatment for NHS/hospital	Costs of analgesics for dressing changes Pressure garment costs	14
	Length of hospital stay	Length of stay adjusted for burn size Days in hospital	7
	Length of stay in intensive care unit	Length of ICU stay	3
	Length of time on life support machine	Duration of mechanical ventilation	1
	Use of medicines to treat symptoms	Pain relief required during dressing changes Opioid consumption	12

FFP, fresh frozen plasma; ICU, intensive care unit; IL, interleukin; NHS, National Health Service.

Discussion

This systematic review aimed to examine outcome reporting in RCTs in burn care. Of the 147 included studies, 1494 outcomes were identified with 955 of these unique. There was overlap in terminology, inconsistent definitions and variation in time after injury at which the outcomes were measured. Only 30% of the outcomes reported were included in more than one study. There was no single outcome reported across all 147 trials. Commonly-reported outcomes were defined differently between trials, such as burn wound healing which was defined in 166 different ways. Such heterogeneity of outcome reporting across trials will limit evidence synthesis and result in research wastage.

The findings in this review have been seen elsewhere in the burns-specific and other clinical literature. A Cochrane review of 30 RCTs concluded that it was impossible to draw conclusions about burn dressing effectiveness, as the trials evaluated a variety of clinical outcomes.18 179 Over the same period as this review, nine Cochrane reviews have had direct relevance to the management of patients with burns.18 180–187 None could draw firm conclusions due to methodological issues including heterogeneity of outcome reporting. Heterogeneity is found in the reporting of outcomes relating to critical care, neurological illness, breast reconstruction surgery, prostate cancer, hip and knee replacement, oesophagectomy surgery, low back pain and in cardiac arrest trials among others.188–195 Variation in the definitions of outcomes has also been found within published studies of other healthcare areas. A systematic review of 90 papers reporting wound infection after general surgical procedures identified 41 definitions for wound infection itself, including three published by expert groups.196 Similarly, a total of 56 definitions were identified from 97 studies reporting anastomotic leak rates after gastrointestinal surgery despite publication of a standard definition 2 years before the beginning of the review.197

In this review, we identified and agreed the grouping of the 955 unique outcomes into 54 outcome domains. There is no agreement between COS reviewers about how best to classify outcomes into domains. Williamson published a taxonomy of categorising outcome domains.198 Other authors have suggested different ways of doing this, all addressing different needs32 33 199). In the Williamson taxonomy, the authors state that of 99 COS studies, 21 applied their own approach to outcome classification and only six used an existing system. As we had identified a large number of different clinical burn outcomes and as the outcomes we extracted did not clearly fall within the Williamson taxonomy, we decided to use our own approach to domain classification. We used five multidisciplinary researchers and a patient working independently, and subsequently together, to bring different views and as little bias as possible to the process.

A solution to the above described variation in outcome reporting across trials, is the development of a COS.21 200 201 A COS is a minimum set of the most important outcomes, agreed and recommended for measurement in all trials for a particular condition.31 32 While not limiting choice, a COS will prespecify a set of outcomes to ensure consistency of reporting and the ability to collate evidence into systematic reviews by allowing researchers to compare ‘like with like’.33 Trials can still select additional outcomes in addition to the minimum core set. This approach has been shown to improve the consistency of outcome reporting.202 203 Although there is no COS for burn care, work was undertaken in 2008 to agree a set of burn outcome domains.198 However, the work was undertaken by a small group of clinicians, lacked patient involvement and reported little methodological detail.204 Considerable work to develop COS methodology has also been undertaken since this publication.205 206 The COMET Initiative disseminates resources for COS development and supports methodological developments in this area.207 208 COMET recommends a four-step process to develop a COS: (a) agreement of the scope, (b) assessment of the need, (c) development of a protocol and finally (d) agreement of the COS.15 This systematic review has satisfied the first two phases for the development of a burn care COS. The final phase encompasses organising a comprehensive long-list of all potential outcomes into domains (of which the clinical domains for burn care are listed in table 4) and prioritising these domains using a consensus process.209–211

The strengths of this review are that the protocol and data extraction proforma were prespecified and the literature search was systematic and comprehensive, including four major healthcare trial databases. To account for multidisciplinary perspectives, two researchers, two clinicians and a patient were involved in the domain process. It is also novel because it is the first to demonstrate, in detail and using systematic methodology, the scale of the heterogeneity of outcome reporting in burn care research. Limitations include the exclusion of publications in languages other than English. However, international publications were included to reduce the risk of selection bias. The search was also time-limited which may have excluded outcomes from older studies. The reason for the time limitation was to identify research relevant to modern burn care. The search was also limited to trials reporting clinical outcomes. Other work is in progress to assess patient-reported outcomes in burn care research. This was a review undertaken systematically to a prespecified protocol. However, a formal quality assessment of studies was not undertaken, as we were researching the reporting of outcomes and not attempting to analyse the effects of interventions. A COS for burn care research would address the issue of heterogeneity of outcome reporting between trials, lead to research that is more likely to measure relevant outcomes, enhance the value of burn care systematic reviews and reduce research waste.

Conclusion

We have shown that multiple different unique outcomes are reported in trials of burn care interventions. Different definitions are used to assess the same outcome issue and outcomes are measured at different time points after injury. This heterogeneity and inconsistency in outcome reporting prevent effective evidence synthesis and limits the quality of evidence available for clinical decision-making. Our review demonstrates that until greater consistency is achieved in outcome reporting in trials, it is unlikely that clinicians will be able to synthesise evidence across studies to understand the effects of surgical and non-surgical treatments following burn injury. It is recommended that a burn care COS is developed to support the effective synthesis of trial data and allow more informed clinical decision-making for the benefit of patients.