Abstract
BackgroundUpregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury. The current study aimed to develop a novel, 24-h, clinically relevant, ovine model of brain death to investigate the profile of the endothelin axis during brain death-associated cardiopulmonary injury. We hypothesised that brain death in sheep would also result in demonstrable injury to other transplantable organs.MethodsTwelve merino cross ewes were randomised into two groups. Following induction of general anaesthesia and placement of invasive monitoring, brain death was induced in six animals by inflation of an extradural catheter. All animals were supported in an intensive care unit environment for 24 h. Animal management reflected current human donor management, including administration of vasopressors, inotropes and hormone resuscitation therapy. Activation of the endothelin axis and transplantable organ injury were assessed using ELISA, immunohistochemistry and standard biochemical markers.ResultsAll animals were successfully supported for 24 h. ELISA suggested early endothelin-1 and big endothelin-1 release, peaking 1 and 6 h after BD, respectively, but there was no difference at 24 h. Immunohistochemistry confirmed the presence of the endothelin axis in pulmonary tissue. Brain dead animals demonstrated tachycardia and hypertension, followed by haemodynamic collapse, typified by a reduction in systemic vascular resistance to 46 ± 1 % of baseline. Mean pulmonary artery pressure rose to 186 ± 20 % of baseline at induction and remained elevated throughout the protocol, reaching 25 ± 2.2 mmHg at 24 h. Right ventricular stroke work increased 25.9 % above baseline by 24 h. Systemic markers of cardiac and hepatocellular injury were significantly elevated, with no evidence of renal dysfunction.ConclusionsThis novel, clinically relevant, ovine model of brain death demonstrated that increased pulmonary artery pressures are observed after brain death. This may contribute to right ventricular dysfunction and pulmonary injury. The development of this model will allow for further investigation of therapeutic strategies to minimise the deleterious effects of brain death on potentially transplantable organs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-015-0067-9) contains supplementary material, which is available to authorized users.
Highlights
Upregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury
arterial oxygen partial pressure (PaO2):fraction of inspired oxygen (FiO2) was 221 ± 81 less in brain death (BD) animals at 1 h and 110 ± 80 less at 2 h. These variables were thereafter similar to controls and no difference was found at 24 h (p = 0.56 P(A-a)O2 and p = 0.87 PaO2:FiO2)
Data is accumulating of the role of ET-1 in brain death and organ donation; activation of the endothelin axis has been demonstrated early in BD-related pulmonary inflammation [8], it contributes to complications associated with human lung donation [12, 36, 37] and it may contribute to the altered cardiopulmonary haemodynamics observed in the current study, similar to other forms of pulmonary hypertension
Summary
Upregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury. Peri-transplant injury contributes to the ongoing shortage of transplantable lungs; this is highlighted by American data reporting an average rate of lungs transplanted per donor of 0.37 [6]. Endothelins, their precursors, receptors and associated signalling pathways are collectively referred to as the endothelin axis [7, 8]. Upregulation of endothelin receptors “primes” the lungs for post-transplant injury [2] and may partly explain the relationship between endothelin expression and primary graft dysfunction that has been observed in human lung allograft recipients [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
