Brain Death-Induced Inflammatory Activity is Similar to Sepsis-Induced Cytokine Release

Abstract

Brain death (BD) is associated with a systemic inflammation leading to worse graft outcomes. This study aimed to compare plasma cytokine values between brain-dead and critically ill patients, including septic and non-septic controls, and evaluate cytokine release kinetics in BD. Sixteen brain-dead and 32 control patients (16 with and 16 without sepsis) were included. Plasma cytokines were measured by magnetic bead assay after the first clinical exam consistent with BD and every 6 hours thereafter, and at the time of study entry in the control group. The values for IL-8 and IFN-γ were higher in brain-dead and septic patients than in non-septic patients [IL-8: 80.3 (18.7–169.6) vs. 68.2 (22.4–359.4) vs. 16.4 (9.2–42.7) pg/mL; P = 0.006; IFN-γ: 2.8 (1.6-6.1) vs. 3.4 (1.2–9.0) vs. 0.5 (0.5–1.8) pg/mL; P = 0.012]. TNF showed a clear tendency to increase in brain-dead patients [2.7 (1.0–4.8) vs. 1.0 (1.0–5.6) vs. 1.0 (1.0–1.0) pg/mL; P = 0.051], and IL-6 values were higher in brain-dead patients than in non-septic controls [174.5 (104.9–692.5) vs. 13.2 (7.3–38.6) pg/mL; P = 0.002]. These differences remained even after excluding brain-dead patients who also had sepsis (n = 3). IL-1β and IL-10 values increased from baseline to time point 2 (∼6 hours later) [IL-1β: 5.39 (1.93–16.89) vs. 7.11 (1.93–29.13) pg/mL; P = 0.012; IL-10: 8.78 (3.62–16.49) vs. 15.73 (5.49–23.98) pg/mL; P = 0.009]. BD-induced and sepsis-induced plasma cytokine values were similarly high, and both were higher than the observed in non-septic critically ill patients.

Development and validation of a quantitative electron microscopy score to assess acute cellular stress in the human exocrine pancreas

“…A trend towards higher EM scores in DCD versus DBD pancreata was also observed across all parameters but this only reached significance for mitochondrial changes, potentially reflecting progressive degradation initiated through warm ischaemia. Whilst the impact of additional warm ischaemia during procurement of DCD organs was smaller than expected, DCD organs have not usually been exposed to the ‘cytokine storm’ following brainstem death which elicits tissue damage similar to changes seen during sepsis [1–3]. Our findings are in keeping with the potential for comparable outcomes to DBD pancreas transplants with appropriate selection of DCD organs [4,7].…”

“…The pancreas is particularly susceptible to acute cellular injury. This is manifest in deceased donor pancreata procured for vascularised whole‐organ and isolated‐islet transplantation which are subject to peri‐mortem ischaemic and inflammatory stress associated with donation after brainstem death (DBD) or warm ischaemia associated with donation after circulatory death (DCD) [1–4]. This is exacerbated by logistically necessary periods of cold ischaemia during organ storage prior to transplantation.…”

A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death

“…No changes in plasma proinflammatory TNFα and IL-1β were evident in our study, which aligns with other reports [ 39 , 44 , 45 ]. Our observation of increased plasma IL-10 reflects observations in BSD patients [ 42 , 46 , 47 ]. However, the delay in activation of IL-10 immunosuppressive actions (> 8 h) is unlikely responsible the unchanged TNFα and IL-1β in our study [ 48 ].…”

In silico deceased donor intervention research: A potential accelerant for progress

“…In the kidney, the activation of WBs fosters the production of IL6 IR , TNFα IR , IL1β IR , and IL10 , regulated in a precise network, 22 which in turn modulate the activation of resident WBs . When the inflammation becomes unregulated (e.g., under septic conditions), pro‐inflammatory cytokines are poured into the bloodstream, further exacerbating the systemic inflammatory state 21 . Finally, activated WB s up‐regulate I , which acts as a pathogen toward WBs by summoning new immune‐cells migration toward the site of injury.…”

“…To illustrate the feasibility of this approach, we built a preliminary in silico model of renal injury after neurologic death calibrated and validated upon data obtained from numerous animal model studies 16‐27 . Furthermore, to demonstrate this type of model's ability to correlate with a well‐described clinical intervention, we used it to perform an in silico simulation of the recent therapeutic hypothermia (TH) trial in deceased donor kidney graft function 28 .…”