Pharmacological interventions for the hemodynamic management of deceased organ donors

Every year, thousands of chronically ill patients are added to the transplant list, in the hope of an organ transplant that could save their life. Most frequently, organ donation occurs following neurological death of a donor, a clinical pathological condition that can jeopardize the quality and stability of organs. The body of literature on the hemodynamic consequences of neurological death and their treatment exist since the early 80’s. Since then, very few randomized trials have been performed on the neurologically deceased donor population. As a consequence, the benefit of routine pharmacological therapies for the hemodynamic management of neurologically deceased donors on recipients’ outcomes is still uncertain, and the pathological theory underlying their use remains questionable.  Consequently, this thesis aims at describing the actual body of evidence supporting the pharmacological treatment for the hemodynamic management of neurologically deceased donors and the theoretical rationale for their use. We also aimed at adding to the actual knowledge of brain death physiological hemodynamic consequences. To achieve this goal, we drew a broad portrait of the actual management of hemodynamic instability in organ donors, leading to the exploration of perceptions on these interventions. We then explored physiological consequences of neurological death at the heart level and evaluated the feasibility of conducting a multicentre trial on a pharmacological intervention in donors. Our thesis let to four research articles.  First, we demonstrated through a systematic review of international guidelines for the management of neurologically deceased donors that the existing recommendations are inconsistent and that their poor methodological quality reflects the slow emergence of clinical research in the field. Then, in a national survey of intensive care physicians with experience in organ donor clinical management, we identified varying perceptions of practices in the country. We attributed this difference in opinions to the paucity of research in the field and to the possible relative inexperience of some physicians when managing deceased donors, a relatively rare condition in the intensive care unit. Our third article suggested that right ventricular dysfunction is frequent after neurological death, although existing literature focus mainly on the occurrence and consequences of left ventricular dysfunction. We postulate that the actual description of hemodynamic consequences of neurological death is incomplete and that a better understanding of the mechanisms underlying right ventricular dysfunction would permit to identify new therapeutic targets. Finally, based on our previous conclusions, we questioned the relevance and efficacy of levothyroxine routine administration in donors and designed a pilot randomized controlled trial to evaluate the feasibility of a multicenter definitive trial. This pilot trial permitted to identify important barriers to interventional research including neurologically deceased donors. We propose that knowledge translation activities on the actual level of evidence supporting routine interventions be implemented in the preparation of a future randomized trial.   This thesis permits to question the validity of the actual pharmacological management of neurologically deceased donors highlighting the paucity of high-evidence literature in the field and the penetrance of historical interventions and concepts. We suggest that the future of research in the field lies on the ability to recognize areas of uncertainties and the acceptance of practice change.

Keyphrases: Neurological death, Organ donation, Hemodynamics, Intensive care unit