The Hemodynamic Mechanisms of Lung Injury and Systemic Inflammatory Response Following Brain Death in the Transplant Donor

Abstract

Brain-dead donors are the major source of lungs for transplantation. Brain death is characterized by two hemodynamic phases. Initially, massive sympathetic discharge results in a hypertensive crisis. This is followed by neurogenic hypotension. Up-regulation of pro-inflammatory mediators occurs in all organs and lung injury develops; this can adversely affect graft function post-transplantation. The mechanisms of the systemic and lung inflammation are unknown. We hypothesized that the hemodynamic changes are responsible for these inflammatory phenomena. Brain death was induced by intra-cranial balloon inflation in rats. This resulted in hypertensive crisis, followed by hypotension. There was a significant increase in blood neutrophil CD11b/CD18 expression and pro-inflammatory cytokine levels in serum and bronchoalveolar lavage, compared with control animals. Rupture of the capillary-alveolar membrane was demonstrated by electron microscopy. Elimination of the hypertensive response by a -adrenergic antagonist pre-treatment prevented inflammatory lung injury, reduced the systemic inflammatory markers and preserved capillary-alveolar membrane integrity. Correction of the neurogenic hypotension with noradrenaline ameliorated the systemic inflammatory response and improved oxygenation. We conclude that the sympathetic discharge triggers systemic and lung inflammation, which can be further enhanced by neurogenic hypotension. Management of the brain-dead donor with early anti-inflammatory treatment and vasoconstrictors is warranted.

Brain death and its implications for management of the potential organ donor

“…[73][74][75] Another effect of this osmotherapy is that it may slow down the herniation process, leading to a less pronounced sympathetic storm with less damage to solid organs and probably less immunological activation. 28 …”

“…Both the sympathetic storm and the hemodynamic instability following brain death seem to be involved in these processes because they can be attenuated experimentally by a-receptor blockade during brain death avoiding the hypertensive crisis, and by norepinephrine or volume loading after brain death avoiding the subsequent hemodynamic instability. 28,[60][61][62] Both the sympathetic storm and the subsequent hemodynamic instability may lead to hypoperfusion and ischemia in various organs and consequently activate the cytokine system. Several cytokines have been found in brain tissue and cerebrospinal fluid after brain injury and through a defective blood-brain barrier, they may reach the circulation and stimulate target cells in the blood and somatic organs.…”

Altered Immunogenicity of Donor Lungs via Removal of Passenger Leukocytes Using Ex Vivo Lung Perfusion

“…This is especially true in the context of lung transplantation, where the lung represents a primary barrier to the external environment and is equipped with a sophisticated immune compartment. In severe cases of injury and inflammation such as brain or cardiac death, a robust systemic immune response ensues (5), which includes pulmonary inflammation manifesting in a local cytokine storm (6) and mass cellular infiltrates (5). Using current strategies for transplantation, it is here that inflamed donor lungs with a globally activated immune system are transplanted into the recipient.…”

A Sphingosine 1–Phosphate 1 Receptor Agonist Modulates Brain Death–Induced Neurogenic Pulmonary Injury

“…However, the early autonomic storm accompanying brain BD triggers the development of systemic and pulmonary inflammatory responses, which lead to increased pulmonary endothelial permeability (1,2) and to the sympathetic vasoconstriction of the systemic and pulmonary vasculature. These changes, in addition to possible ischemiareperfusion injury, disrupt the integrity of the alveolar capillary membrane, resulting in neurogenic pulmonary edema (NPE) (1)(2)(3)(4). Increased pulmonary interstitial and alveolar fluid accumulation usually develops rapidly after acute injury to the central nervous system (1), and any preventive treatment should be given early after BD (3).…”