Preclinical septic shock research: why we need an animal ICU

Abstract

Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using—in case of rats and mice—miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.

Microcirculation vs. Mitochondria—What to Target?

“…They undertook a meta-analysis reviewing both experimental models and clinical studies and reported variable results on mitochondrial function depending on the species, organ, and time point investigated ( 90 ). However, the available experimental literature mainly originates from young and otherwise healthy animals, which does not represent the more frequent clinical scenario of elderly patients with comorbidities, a common pitfall of experimental studies in shock research in general ( 43 ). Nevertheless, there is elegant clinical evidence that despite adequate resuscitation, reduced mitochondrial respiration is (i) present in patients after the initial management of circulatory shock, and (ii) associated with worse outcomes.…”

“…Based on this rationale, fluid resuscitation ( 30 – 34 ), dobutamine ( 35 ), levosimendan ( 36 ), milrinone ( 37 ), nitric oxide (NO) donors ( 38 – 40 ), and prostacyclin (PGI 2 ) ( 40 – 42 ) have all been tested. In experimental settings, this approach was often successful but the majority of animal studies were only of short duration and/or did not include standard intensive care measures, which may limit transferability into clinical practice ( 43 ). Given the potential NO- or NO-derivatives induced uncoupling of mitochondrial respiration and inhibition of complex I and complex IV ( 14 , 44 – 46 ), caution must be taken with NO-donors as a therapeutic strategy to avoid detrimental effects on the mitochondria.…”

Inducing Experimental Polymicrobial Sepsis by Cecal Ligation and Puncture

“…Current Protocols in Immunology sepsis models, including the use of antibiotics, fluid resuscitation, and monitoring of vital processes (Guillon et al, 2019).…”

Rethinking animal models of sepsis – working towards improved clinical translation whilst integrating the 3Rs

“…Here, we suggest that the most translational sepsis model is used, e.g. an animal model with full intensive care unit (ICU) support [117].…”