A brain death model with slow induction for experimental studies of organ donation

Aim. To test in experiment a pathogenetically adequate model of brain death due to increased intracranial pressure with gradual induction, allowing the evaluation of the changes occurring in the organs of a potential donor.

Materials and methods. 6–8 months old outbred male rats of the experimental group (n = 18) and the control group (n = 8) were anesthetized, the left common carotid artery was catheterized to record systolic, diastolic blood pressure (BP) and heart rate (HR), the mean BP (MBP) was calculated. After transfer to artifi cial ventilation, brain death was simulated in the experimental group using the developed method.

Results. All animals in the experimental group suffered brain death 30 minutes from the start of the experiment;10 rats (56%) died within 3 hours due to progression of circulatory failure. Initially, in anesthetized animals, MBP was 101 (90; 105) mm Hg, HR 310 (297; 315) beats/min. After 5 minutes from the start of brain death induction, MBP increased to 147 (140; 150) mm Hg (p = 0.01), HR to 396 (384; 406) beats/min (p = 0.03). Further, within 20 minutes there was a decrease in MBP to 94 (90; 100) mm Hg and HR to 290 beats/min. During the observation period from 26 to 90 minutes, there was a stabilization of MBP at the level of 87–92 mm Hg, there was a tendency to bradycardia with HR from 263 to 274 beats/min (p = 0.01). Then after 120–150 minutes from the beginning of brain death induction, MBP continued to decrease to 75–80 mmHg (p = 0,03), HR to 256–264 beats/min (p = 0,01). At the end of the experiment, despite volemic support, MBP decreased to 64 (61; 67) mm Hg (p = 0.02), bradycardia worsened with HR to 250 (248; 260) beats/min (p = 0.01), indicating the hemodynamic decompensation.

Conclusion. The results of experimental testing of an animal brain death model on outbred rats showed that this model is pathogenetically adequate and useful to assess the condition of potential donor organs within 3 hours after the induction of brain death.

1. Guo Z., Luo T., Mo R., et al. Ischemia-free organ transplantation – a review. Curr Opin Organ Transplant. 2022 Aug 1; 27(4): 300– 304. https://doi.org/10.1097/MOT.0000000000000998. Epub 2022 Jul 5. PMID: 36354255

2. Yoshikawa M.H., Rabelo N.N., Welling L.C., et al. Brain death and management of the potential donor. Neurol Sci. 2021 Sep; 42(9): 3541–3552. https://doi.org/10.1007/s10072-021-05360-6. Epub 2021 Jun 17. PMID: 34138388; PMCID: PMC8210518

3. Zens T.J., Danobeitia J.S., Chlebeck P.J., et al. Guidelines for the management of a brain death donor in the rhesus macaque: A translational transplant model. PLoS ONE 2017 Sep 19; 12(9): e0182552. https://doi.org/10.1371/journal.pone.0182552. PMID: 28926566; PMCID: PMC5604963

4. Esmaeilzadeh M., Sadeghi M., Heissler H.E., et al. Experimental rat model for brain death induction and kidney transplantation. J Invest Surg. 2020 Feb; 33(2): 141–146. https://doi.org/10.1080/08941939.2018.1480677. Epub 2018 Oct 18. PMID: 30335532

5. Petersen A., Soderstrom M., Saha B., Sharma P. Animal models of traumatic brain injury: a review of pathophysiology to biomarkers and treatments. Exp Brain Res. 2021 Oct; 239(10): 2939–2950. https://doi.org/10.1007/s00221-021-06178-6. Epub 2021 Jul 29. PMID: 34324019

6. Percie du Sert N., Ahluwalia A., Alam S., et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020 Jul 14; 18(7): e3000411. https://doi.org/10.1371/journal.pbio.3000411. PMID: 32663221; PMCID: PMC7360025

7. Lopez-Jimenez F., Pniagua D., Lamas G.A. La interpretación de los ensayos clínicos negativos [Interpretation of negative clinical trials]. Rev. Invest. Clin. 1998 Sep-Oct; 50(5): 435–440. Spanish. PMID: 9949676

8. Ермолаев П.А., Храмых Т.П. Патент РФ RU 2798902 С1, Способ моделирования смерти головного мозга в эксперименте. Опубликовано: 28.06.2023 Бюл. № 19

9. Clarke C., Management of the brain-dead organ donor. Indian J Thorac Cardiovasc Surg. 2021 Sep; 37(Suppl 3): 395–400. https://doi.org/10.1007/s12055-021-01224-y. Epub 2021 Sep 17. PMID: 34548770; PMCID: PMC8445737

10. Jurcau A., Simion A. Neuroinfl ammation in cerebral ischemia and ischemia/reperfusion injuries: from pathophysiology to therapeutic strategies. Int J Mol Sci. 2021 Dec 21; 23(1): 14. https://doi.org/10.3390/ijms23010014. PMID: 35008440; PMCID: PMC8744548

11. Pomper G., Trescher K., Santer D., et al. Introducing a mouse model of brain death. J Neurosci Methods. 2010 Sep 30; 192(1): 70–74. https://doi.org/10.1016/j.jneumeth.2010.07.019. Epub 2010 Jul 23. PMID: 20655951

12. Kalra S., Malik R., Singh G., et al. Pathogenesis and management of traumatic brain injury (TBI): role of neuroinfl ammation and anti-infl ammatory drugs. Infl ammopharmacology. 2022 Aug; 30(4): 1153–1166. https://doi.org/10.1007/s10787-022-01017-8. Epub 2022 Jul 8. PMID: 35802283; PMCID: PMC9293826

13. Visser K., Koggel M., Blaauw J., et al. Blood-based biomarkers of infl ammation in mild traumatic brain injury: A systematic review. Neurosci Biobehav Rev. 2022 Jan; 132: 154–168. https://doi.org/10.1016/j.neubiorev.2021.11.036. Epub 2021 Nov 23. PMID: 34826510

14. Виноградов В.Л. Актуальные вопросы органного донорства. Введение. Лекция. Трансплантология. 2013; 4: 15–23

15. Feng D., Lewis A. Brain death: ethical and legal challenges. Neurol Clin. 2023 Aug; 41(3): 469–483. https://doi.org/10.1016/j.ncl.2023.03.004. Epub 2023 Apr 20. PMID: 37407100

16. Walweel K., Boon A.C., See Hoe L.E., et al. Brain stem death induces pro-infl ammatory cytokine production and cardiac dysfunction in sheep model. Biomed J. 2022 Oct; 45(5): 776–787. https://doi.org/10.1016/j.bj.2021.10.007. Epub 2021 Oct 16. PMID: 34666219; PMCID: PMC9661508

17. Alsbrook D.L., Di Napoli M., Bhatia K., et al. Neuroinfl ammation in acute ischemic and hemorrhagic Stroke. Curr Neurol Neurosci Rep. 2023 Aug; 23(8): 407–431. https://doi.org/10.1007/s11910023-01282-2. Epub 2023 Jul 3. PMID: 37395873; PMCID: PMC10544736

18. Marasco S., Kras A., Schulberg E., et al. Donor brain death time and impact on outcomes in heart transplantation. Transplant Proc. 2013 Jan-Feb; 45(1): 33–37. https://doi.org/10.1016/j.transproceed.2012.08.008. PMID: 23375272

19. Tsai Y.H., Lin J.Y., Huang Y.Y., Wong J.M. Cushing response-based warning system for intensive care of brain-injured patients. Clin Neurophysiol. 2018 Dec; 129(12): 2602–2612. https://doi:10.1016/j.clinph.2018.09.010. Epub 2018 Sep 21. PMID: 30453271

20. Ng S.Y., Lee A.Y.W. Traumatic brain injuries: pathophysiology and potential therapeutic targets. Front Cell Neurosci. 2019 Nov 27; 13: 528. https://doi.org/10.3389/fncel.2019.00528. PMID: 31827423; PMCID: PMC6890857