Neurogenic Fever after Subarachnoid Hemorrhage in Animal Models: A Systematic Review

Abstract

The observation of neurogenic fever resulting from subarachnoid hemorrhage (SAH) in animal models is a useful tool for the interpretation of its pathophysiology in humans, which is still a major challenge in the management of neurocritical patients. This systematic review aims to identify the prognostic factors and pathophysiological elements that determine the onset of neurogenic fever and its severity in animal models. In addition, our study aims to analyze which pharmacological treatments are most effective. All the articles available in Pubmed, Embase, and the Biological Science Collection until August 2021 concerning in vivo experimental studies on SAH animal models, including full texts and abstracts written in English and Italian, were considered. The risk of bias was assessed with SYRCLE’s Risk of Bias tool. In total, 81 records were retrieved; after excluding duplicates, 76 records were potentially relevant. A total of 64 articles was excluded after title and abstract screening. The remaining 12 studies were evaluated as full texts, and 6 other studies were excluded (SAH-induced animal studies without a body temperature assessment). In one study, body temperature was measured after SAH induction, but the authors did not report temperature recording. Therefore, only five studies met the search criteria. The high methodological heterogeneity (different animal species, different temperature measurement methods, and different methods of the induction of bleeding) prevented meta-analysis. Synthesis methodology without meta-analysis (SWiM) was used for data analysis. The total number of animals used as controls was 87 (23 rabbits, 32 mice, and 32 rats), while there were 130 animals used as interventions (54 rabbits, 44 mice, and 32 rats). The presence of blood in the subarachnoid space, particularly red blood cells, is responsible for neurogenic fever; the role of hemoglobin is unclear. The mechanism is apparently not mediated by prostaglandins. The autonomic nervous system innervating brown adipose tissue is undoubtedly implicated in the onset of neurogenic fever. The activation of the central adenosine-1 receptor is effective in controlling the temperature of animals with neurogenic fever (by inhibiting thermogenesis of brown adipose tissue).