Transforming research to improve therapies for trauma in the twenty-first century: an alternative perspective

Revolution in sepsis: a symptoms-based to a systems-based approach?

“…We have shown the drug shifts sympathetic hyperactivity to parasympathetic dominance in the rat model of non-compressible hemorrhagic shock [ 96 ], restores cardiac output [ 97 ], protects against endothelial glycocalyx shedding with 97% rapid restoration [ 169 ], and reduces the incidence of MODS [ 50 , 98 ]. During resuscitation, we have shown the ALM therapy is neuroprotective at hypotensive pressures (MAPs 47–50 mmHg), which has important implications for sepsis [ 50 – 53 , 97 , 98 ]. This data has been use to formulate a Systems Hypothesis of Trauma (SHOT), which may be applicable for sepsis and septic shock [ 49 , 50 , 54 ].…”

“…We begin our systems analysis of sepsis with the central nervous system (CNS) as it is the hierarchical controller of whole-body homeostasis through the multiple feedback circuits (or axes) linking the O 2 we breathe to mitochondrial ATP production. The term 'systems' refers to the whole body's response to an infection, which includes its activation, progression and outcome [51][52][53]. A systemsacting drug is defined as one that treats the pathophysiological response from a systems' perspective (see later).…”

“…Why have there been so few advances in pre-clinical drug development for sepsis and translation to humans? Three possible reasons include: 1) the widespread use of specific-pathogen free (SPF) animal models with their altered microbiomes and immature immune systems that do not represent the human condition [45,47,48,[51][52][53], Conventionally bred and housed animals should be used if human translation is the end-game [51][52][53], 2) the flawed practice of the treat-as-you go mindset and single nodal drug targeting, which ignores the complexity of the system [49][50][51][52][53][54], and 3) poor clinical trial design that does not represent the heterogeneity of patient responses to sepsis [21,143]. With respect to single-nodal targets, we will give one example.…”

“…A drug that inhibits the IL-1-receptor, anakinra, has an excellent safety record in humans, however, it has failed to show a survival benefit after sepsis or COVID-19 [149,150]. The 'single-step' drug target approach can be traced back to the molecular revolution of the 20th century, which began in around 1953 after the discovery of DNA [51][52][53]. Nobel Laureate Sir Francis Crick embodied this highly mechanistic mindset when he wrote "the ultimate aim of the modern movement in biology is to explain all biology in terms of physics and chemistry" [29].…”

“…Nobel Laureate Sir Francis Crick embodied this highly mechanistic mindset when he wrote "the ultimate aim of the modern movement in biology is to explain all biology in terms of physics and chemistry" [29]. From a molecular standpoint Crick was correct, however, its relevance to the workings of the whole body has not kept pace [51][52][53]. The advent of the "Omic" technologies to drill deeper into molecular mechanisms has occurred at the expense of systems analysis.…”