79 Review Inflammatory Mediators in Animal Burn Models and can stimulate the design of targeted interventions such as removal of inflammatory triggers, cytokine blockade or regulation of immune cells to improve treatment for burn patients. MATERIALS AND METHODS Study protocol and eligibility criteria The associated review protocol was established beforehand and registered at the International Prospective Register of Systematic Reviews (PROSPERO) [78] under number CRD42019136270 (http://www.crd.york.ac.uk/PROSPERO/display_record. php?RecordID=136270). We amended this protocol once to further specify the metaanalyses. Search strategy The search was performed using PubMed and Embase according to the guidelines of Leenaars et al. [79], with a final update on August 17, 2022. The search strategy (search string) from Mulder et al. [8] was used. Briefly, articles with primary data on the immune response in animals with burn injury were searched using the following search components: burn injury, immune response, and animal. No restrictions were applied regarding language or publication date. Search results were combined and duplicate records were removed using EndNote software (X9, Clarivate Analytics, London, United Kingdom). Study selection Studies were selected by PPGM and BKHLB in blinded fashion using Rayyan software (Rayyan Systems, Cambridge, MA) [80] divided over three rounds: title screening, abstract screening, and full-text screening. During the title screening, articles clearly unrelated to burn injury were excluded. In the abstract screening, we selected studies that involved animal skin burns that contained primary data. Reviews, posters, and conference abstracts were excluded in this round. Selected studies for which the full text was inaccessible were excluded. During the full-text screening, studies involving animal thermal injuries with outcome measures related to inflammatory mediators were selected. Studies that used other burn types such as frostbite, chemical or electrical injuries were excluded. Furthermore, studies with co-interventions that obviously interfered with the function of the immune system, such as infection or administration of pro- or anti-inflammatory therapeutics were excluded. Additionally, the use of an appropriate control group (i.e. sham controls, uninjured animals, baseline values, or samples of uninjured tissue from same animals) was verified. At each screening round 3
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