FIGURE 7.

The ‘switch’ hypothesis proposes that ALM therapy transitions the injury phenotype to a survival phenotype in the first few minutes to hours after major trauma. The switch involves re-setting or rebalancing the innate immune and inflammatory responses to the surge and ongoing releases of DAMPs, and other damage signals, into the circulation from the trauma. Implicit to the hypothesis is the assumption that the hyperacute immune and inflammatory events that occur in first few minutes to hours following a major trauma pre-determine the trajectory of the later immune and inflammatory responses and outcome. Timely resolution of the immune and inflammatory ‘storms’ appears to be key. Although the mechanisms are unknown, one potential target are monocytes which have recently been shown to sense injury-released DAMPs via the AIM2 inflammasome and induce the extrinsic cell death of T cells (Roth et al., 2021). ALM, adenosine, lidocaine and magnesium; CNS, central nervous system; DAMP, damage-associated molecular pattern; IL, interleukin; PIICS; Persistent Inflammation, Immunosuppression and Catabolism Syndrome.