Systemic PaO2 Oscillations Cause Mild Brain Injury in a Pig Model

Abstract

OBJECTIVE: Systemic PaO2 oscillations occur during cyclic recruitment and derecruitment of atelectasis in acute respiratory failure and might harm brain tissue integrity. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Adult anesthetized pigs. INTER-VENTIONS: Pigs were randomized to a control group (anesthesia and extracorporeal circulation for 20 hr with constant PaO2, n = 10) or an oscillation group (anesthesia and extracorporeal circulation for 20 hr with artificial PaO2 oscillations [3 cycles min¹], n = 10). Five additional animals served as native group (n = 5). MEASUREMENTS AND MAIN RESULTS: Outcome following exposure to artificial PaO2 oscillations compared with constant PaO2 levels was measured using 1) immunohistochemistry, 2) real-time polymerase chain reaction for inflammatory markers, 3) receptor autoradiography, and 4) transcriptome analysis in the hippocampus. Our study shows that PaO2 oscillations are transmitted to brain tissue as detected by novel ultrarapid oxygen sensing technology. PaO2 oscillations cause significant decrease in NISSL-stained neurons (p < 0.05) and induce inflammation (p < 0.05) in the hippocampus and a shift of the balance of hippocampal neurotransmitter receptor densities toward inhibition (p < 0.05). A pathway analysis suggests that cerebral immune and acute-phase response may play a role in mediating PaO2 oscillation-induced brain injury. CONCLUSIONS: Artificial PaO2 oscillations cause mild brain injury mediated by inflammatory pathways. Although artificial PaO2 oscillations and endogenous PaO2 oscillations in lung-diseased patients have different origins, it is likely that they share the same noxious effect on the brain. Therefore, PaO2 oscillations might represent a newly detected pathway potentially contributing to the crosstalk between acute lung and remote brain injury.

Cyclic PaO2 oscillations assessed in the renal microcirculation: correlation with tidal volume in a porcine model of lung lavage

“…Systemic PaO 2 oscillations are also transmitted to the cerebral tissue [10]. Long-term exposure to PaO 2 oscillations furthermore causes neuronal injury and inflammatory response within the brain, [6] which may represent a mechanism of deleterious organ crosstalk following single organ failure. Acute kidney injury is the most common organ failure in intensive care units [26].…”

“…In previously published animal models that focused on occurrence and behavior of cRD-related PaO 2 oscillations aggressive ventilator settings with highest tidal volumes were applied to provoke substantial cyclically recruitment of lung tissue [6, 8, 11–13, 23, 30]. The present study is the first one to focus on the tidal volume as a primary driving force for this phenomenon: a down-titration of the applied tidal volume to 10 ml/kg eliminates the PaO 2 oscillations.…”

“…The underlying pathways are not fully understood, but are likely linked to increased inflammation [5]. Respiratory cycle-dependent recruitment and derecruitment of lung parenchyma (cRD), defined as atelectotrauma, plays an important role in ventilator-induced lung injury by applying shearing forces to lung tissue, which lead to pulmonary and/or systemic inflammation [6]. In addition to pulmonary injury, cRD generates varying shunt fractions within the respiratory cycle that lead to ultrafast oscillations of the arterial oxygen partial pressure (PaO 2 ) and can be detected in macrocirculation, microcirculation, and even in brain tissue [7–10].…”

“…Preclinical data suggest that the occurrence of intermitting oxygen oscillations per se might represent a trigger for remote organ failure following lung injury [6, 16–19]. The role of the tidal volume as driving force for PaO 2 oscillations, their transmission to various distant organ microcirculatory sites and particularly the kidney is yet unknown.…”

Peer Review #2 of "Random allogeneic blood transfusion in pigs: characterisation of a novel experimental model (v0.1)"

“…The hypothesis of inflammatory mediator distribution is promising as several studies show inflammatory response after a primary hit. The blood stream seems to be the distributor in remote organ injury and cross-talk (Hegeman et al 2009;Klein et al 2016;Mrozek et al 2015). In theory, inflammatory cytokines that are released into the systemic circulation induce remote organ injury.…”