The implications of brain death in donor lung injury: investigation and blockade of the endothelin axis

Watts, Ryan P. (2016). The implications of brain death in donor lung injury: investigation and blockade of the endothelin axis MPhil Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2016.98

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Author Watts, Ryan P.
Thesis Title The implications of brain death in donor lung injury: investigation and blockade of the endothelin axis
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2016.98
Publication date 2016-02-26
Thesis type MPhil Thesis
Supervisor John F. Fraser
Total pages 153
Total colour pages 3
Total black and white pages 150
Language eng
Subjects 1102 Cardiovascular Medicine and Haematology
1103 Clinical Sciences
0606 Physiology
Formatted abstract
Background: Lungs donated for transplantation are primarily sourced from brain dead organ donors. The process of brain death causes lung injury through haemodynamic instability, catecholamine fluctuations and activation of inflammatory pathways. Recent literature has implicated endothelin-1 in transplantation related lung dysfunction. Therefore, inhibition of endothelin signalling may reduce or reverse endothelin related vasoconstriction and inflammation. Tezosentan, a dual endothelin antagonist, is able to be nebulised to directly target the lungs. This aims to avoid systemic adverse effects, specifically hypotension. Nebulised tezosentan has been previously demonstrated to reduce pulmonary hypertensive responses to systemic inflammatory states.

Objective: This thesis sought to investigate the role of the pulmonary endothelin axis after brain death in a novel, clinically relevant, ovine model of brain death. Furthermore, the effects of nebulised tezosentan on pulmonary haemodynamics and inflammation in donor lungs after brain death were assessed.

Twenty-four merino cross ewes were randomised into four equal groups (n=6 per group). These were control/placebo, control/tezosentan, brain dead/placebo and brain dead/tezosentan. Following induction of general anaesthesia and placement of invasive monitoring, brain death was induced in allocated animals by inflation of an extradural catheter. Animals were then supported in an intensive care unit environment for 24 hours. Management reflected human donor management, including administration of vasopressors, inotropes and hormonal resuscitation therapy. Nebulised tezosentan was administered at 13 and 18 hours. The endothelin axis, and the effects of its antagonism, was assessed by physiological monitoring, blood gas analysis, ELISA, histology and immunohistochemistry. Injury of other organs was assessed using standard biochemical markers.

A total of 25 animals underwent the experimental protocol. One animal died during induction of brain death from ventricular fibrillation and was replaced. Early evidence of endothelin-1 and big endothelin-1 elevations were seen in brain dead animals that received placebo, reaching maximal levels at one and six hours after brain death, respectively. This was not replicated in the brain dead animals that received tezosentan. Systemic endothelin-1 levels were not increased by tezosentan administration. Immunohistochemistry identified the endothelin axis in pulmonary tissue, but this was not different between groups. Induction of brain death resulted in tachycardia and hypertension, followed by haemodynamic collapse. Mean pulmonary artery pressure rose significantly at induction (186 ± 20%) and remained elevated throughout the protocol in those that received placebo. Additionally, right ventricular stroke work increased 25.9% above baseline by 24 hours. Mean pulmonary blood pressure in brain dead animals that received tezosentan showed similar elevations with induction of brain death, but was significantly lower at 24 hours compared to those that received placebo. Systemic markers of cardiac and hepatocellular injury were significantly elevated in brain dead animals, with no evidence of renal dysfunction. Tezosentan administration did not adversely affect systemic haemodynamics and there was no evidence of adverse effects on remote organs.

Conclusions: This novel, clinically relevant, ovine model demonstrated that the endothelin axis is able to be modulated after brain death, reducing the observed elevations in pulmonary blood pressure. Early endothelin release possibly contributes to the previously recognised inflammation and cardiopulmonary injury in potential donors. Further investigation is required to determine the exact mechanism of the observed results. In the future, antagonism of the endothelin axis after brain death may lead to novel treatments that improve the function of pulmonary and cardiac allografts for transplantation.
Keyword Brain Death
Organ transplantation
Pulmonary circulation
Right ventricular function
Circulatory and Respiratory Physiology
Endothelin Receptors

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Created: Sun, 14 Feb 2016, 23:38:57 EST by Ryan Watts on behalf of Learning and Research Services (UQ Library)