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Background: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the b-adrenergic receptor. Phenylephrine, generally regarded as a selective a-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through b-adrenergic affinity.Methods: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and aand b-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30e50 mg kg À1 min À1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg -1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 mg kg À1 min À1 ) or saline before receiving LPS (2 ng kg À1 i.v.). Results: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with b-antagonists, but not a-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (þ42%, P¼0.0069), spleen (þ59%, P¼0.04), and liver (þ35%, P¼0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (þ76%, P¼0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (e15%, P¼0.03).Conclusions: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the b-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. Clinical trial registration: NCT02675868 (Clinicaltrials.gov).

Background Reducing the number of animals used in experiments has become a priority for the governments of many countries. For these reductions to occur, animal-free alternatives must be made more available and, crucially, must be embraced by researchers. Methods We conducted an international online survey for academics in the field of animal science ( N = 367) to explore researchers’ attitudes towards the implementation of animal-free innovations. Through this survey, we address three key questions. The first question is whether scientists who use animals in their research consider governmental goals for animal-free innovations achievable and whether they would support such goals. Secondly, responders were asked to rank the importance of ten roadblocks that could hamper the implementation of animal-free innovations. Finally, responders were asked whether they would migrate (either themselves or their research) if increased animal research regulations in their country of residence restricted their research. Results While nearly half (40%) of the responders support governmental goals, the majority (71%) of researchers did not consider such goals achievable in their field within the near future. In terms of roadblocks for implementation of animal-free methods, ~ 80% of the responders considered ‘reliability’ as important, making it the most highly ranked roadblock. However, all other roadblocks were reported by most responders as somewhat important, suggesting that they must also be considered when addressing animal-free innovations. Importantly, a majority reported that they would consider migration to another country in response to a restrictive animal research policy. Thus, governments must consider the risk of researchers migrating to other institutes, states or countries, leading to a ‘brain-drain’ if policies are too strict or suitable animal-free alternatives are not available. Conclusion Our findings suggest that development and implementation of animal-free innovations are hampered by multiple factors. We outline three pillars concerning education, governmental influence and data sharing, the implementation of which may help to overcome these roadblocks to animal-free innovations. Electronic supplementary material The online version of this article (10.1186/s41073-019-0067-5) contains supplementary material, which is available to authorized users.

17 Reducing the number of animals used in experiments has become a priority for the 18 governments of many countries. For these reductions to occur, animal-free alternatives must 19 be made more available and, crucially, must be embraced by researchers. We conducted an 20 international online survey for academics in the field of animal science (N=367) to explore 21 researchers' attitudes towards the implementation of animal-free innovations. 22 Through this survey we address three key questions. The first question is whether scientists 23 who use animals in their research consider governmental goals for animal-free innovations 24 achievable and whether they would support such goals. Secondly, responders were asked to 25 rank the importance of ten roadblocks that could hamper the implementation of animal-free 26 innovations. Finally, responders were asked whether they would migrate (either themselves 27 or their research) if increased animal research regulations in their country of residence 28 restricted their research. While nearly half (40%) of the responders support governmental 29 goals, the majority (71%) of researchers did not consider such goals achievable in their field 30 within the near future. In terms of roadblocks for implementation of animal-free methods, 31~80% of the responders considered 'reliability' as important, making it the most highly ranked 32 roadblock. However, all other roadblocks were reported by the majority of responders as 33 somewhat important, suggesting that they must also be considered when addressing animal-34 free innovations. Importantly, a majority reported that they would consider migration to 35 another country in response to restrictive animal research policy. Thus, governments must 36 consider the risk of researchers migrating to other institutes, states or countries, leading to a 37 'brain-drain' if policies are too strict or suitable animal-free alternatives are not available. Our 38 findings suggest that development and implementation of animal-free innovations are 39 hampered by multiple factors. We outline three pillars concerning education, governmental 40 influence and data sharing, the implementation of which may help to overcome these 41 roadblocks to animal-free innovations. 42 Introduction 43 Animal research has played a critical role in many scientific and medical achievements of the 44 past century. Animal models are used across many fields, including fundamental, biomedical, 45 behavioural, military and agricultural research [1]. Around the world, quality of life has been 46 greatly improved by the research, medicines, treatments and safer environments that have 47 been developed as a consequence of animal-based research in these fields. However, the 48 ethical issues associated with using animals and increased concern regarding animal 49 wellbeing [2], together with concerns regarding the translatability of animal models [3] and 50 practical difficulties of using animals [4], are gaining importance. In line with this, the 51 principles of 3R (Replacement...

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