38 Chapter 2 close to the human condition in terms of similar skin characteristics and physiology, porcine models are less attractive because of ethical concerns, higher expenses, and advanced operating requirements [38]. Subgroup analyses revealed that blood leukocyte and neutrophil counts were more abundant in rats than in mice. Because rats are larger animals, require a longer healing time, and are immunologically more similar to humans than mice [39], they might exhibit a more severe immune response than mice. In addition, murine studies generally analyzed the effects shortly after burn injury, thereby causing an overrepresentation of early sampling times. The severity of leukocytosis seemed to increase with animal age and may be explained by the fact that a young, underdeveloped immune system is supposedly tolerant and becomes gradually more active during maturity [40]. Interestingly, neutrophil responses appeared to depend on burn size and agent. The relationships between the burn size and inflammatory response in humans have been proposed before by others [35,41,42]. Metal burns induced a greater total leukocyte and neutrophil response in wound tissue than scalds. Water, mostly used at 100 °C, loses heat more rapidly and might therefore cause a less severe injury than metal. It was hardly possible to explore the differences related to wound depth because the majority of studies applied a full-thickness burn wound. Although most studies reported full-thickness injuries, only a limited number of studies actually investigated the wound depth. In addition, wound depth is more prone to subjectivity and depends on many factors such as skin thickness, burn temperature, and duration. Therefore, wound depth was a less useful parameter in these studies. Numerous studies failed to adhere to the Animal Research: Reporting of In Vivo Experiments guidelines [43] and did not provide important experimental details or information on the number of animals or SDs, which are crucial to performing metaanalyses. The inability to apply blinding might have influenced the data acquisition, and owing to the poor reporting of studies, the general RoB was largely unclear. The improper design, conduct, and reporting in many animal studies have already been described in recent reviews [44–46], and future research will surely benefit from more standardized design and reporting [47]. Researchers have shown that resuscitation and pain treatment can influence immune reactions after thermal injury [48,49]. Owing to large variation in the type of anesthetic, resuscitation procedure, and pain management, specific effects on the immune response could not be investigated. Likewise, subgroup analysis of the different methods used to identify cell types was not possible. The overall cell counts showed substantial heterogeneity (I2 = 68‒92), which can be expected for animal studies [50]. In a few subgroup analyses, a trivial reduction of the I2 statistic could be detected. Although animal studies provide valuable insight into the post burn immune response and wound repair, appropriate translation of these findings to the human situation remains
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