Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions


  • Sonay Oğuz Department of Cardiovascular Surgery, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey
  • Halil F. Aşgün Department of Cardiovascular Surgery, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey
  • Başak Büyük Department of Histology and Embryology, Faculty of Medicine, İzmir Democracy University, İzmir, Turkey




HTK solutions, brain ischemia, brain protection.


Background: Tissue-protective solutions increase resistance of cells to ischemic conditions. Especially in carotid and aortic arch surgeries where the brain perfusion is at risk, these solutions may be beneficial to prevent ischemic brain damage. This study was designed to demonstrate the effectiveness of histidine-tryptophan-ketoglutarate (HTK) solution in increasing resistance of brain tissue to ischemic conditions.

Methods: Three separate randomized groups were created, each consisting of eight rabbits. The groups were called the ischemia, HTK and sham groups, respectively. In the ischemia group, temporary brain ischemia was created for 15 minutes by placing clamps on the bilateral subclavian and common carotid arteries. Then the clamps were removed, and the brain was reperfused for 30 minutes. In the HTK group, HTK solution was sent to the brain through the internal carotid artery before the same ischemia-reperfusion protocol was applied. Histopathological analyses using a visual scoring system to assess the degree of ischemic changes and the apoptotic cell index by TUNEL test were performed in all brain tissue samples.

Results: Apoptotic cell indices of the HTK (20.6%) and sham (17.8%) groups were lower than the ischemia group (56.8%) (P < .05). Statistically significant differences were detected between all groups in categorical scores (P < .05).

Conclusions: It was shown that less ischemic damage occurs in the brain tissue with the use of HTK solution, and it may be a candidate approach to prevent the brain from ischemic insults during cerebrovascular surgery. Further studies are required to demonstrate its exact effectiveness, in terms of dose, duration, and temperature.


Agarwal A, Murdock P, Fridell JA. 2006. Comparison of histidine-tryptophan ketoglutarate solution and University of Wisconsin solution in prolonged cold preservation of kidney allografts. Transplantation 81:480-482.

Arslan A, Sezgin A, Gultekin B, Ozkan S, Akay T, Uguz E, et al. 2005. Low-dose histidine-tryptophan-ketoglutarate solution for myocardial protection. In Transplantation proceedings 37:3219-3222.

Bai S, Sun Y, Wu L, Wu Z, Fang M. 2016. Tripotolide ameliorates inflammation and apoptosis induced by focal cerebral ischemia/reperfusion in rats. Med JZU 45:493-500.

Bretschneider HJ. 1980. Myocardial protection. Thorac Cardiovasc Surg 28:295-302.

Chen J, Liu L, Zhang H, Geng X, Jiao L, Li G, et al. 2016. Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke 47:1933-1935.

Choi JH, Pile-Spellman J. 2018. Selective brain hypothermia. In Handbook of clinical neurology 157:839-852.

Edelman JJ, Seco M, Dunne B, Matzelle SJ, Murphy M, Joshi P, et al. 2013. Custodiol for myocardial protection and preservation: a systematic review. Ann Cardiothorac Surg 2:717-28.

Englesbe MJ, Moyer A, Kim DY, Granger DK, Pietroski R, Yoshida A, et al. 2006. Early Pancreas Transplant Outcomes with Histidine-Tryptophan-Ketoglutarate Preservation: A Multicenter Study, Transplantation 82:136-13.

Englum BR, Andersen ND, Husain AM, Mathew JP, Hughes GC. 2013. Degree of hypothermia in aortic arch surgery–optimal temperature for cerebral and spinal protection: deep hypothermia remains the gold standard in the absence of randomized data. Annals of Cardiothoracic Surgery 2:184.

Gokalp O, İner H, Karakas NY, Iscan S, Gokalp G, Besir Y, et al. 2019. Deep Hypothermic Circulatory Arrest in Aortic Dissection Surgery. Heart, Lungand Circulation 28:10-11.

Goodney PP, Wallaert JB, Scali ST, Stone DH, Patel V, Shaw P, et al. 2012. Impact of practice patterns in shunt use during carotid endarterectomy with contralateral carotid occlusion. Journal of Vascular Surgery 55:61-71.

Hoyer A, Then BF, Klaeske K, Lehmann S, Misfeld M, Borger M, et al. 2019. Custodiol-N™ cardioplegia lowers cerebral inflammation and activation of hypoxia-inducible factor-1α. Interactive Cardiovascular and Thoracic Surgery 28:884-892.

Hsu J, Wang C, Huang S, Chen Y, Yu S, Huang J, et al. 2018. Histidine-Tryptophan-Ketoglutarate Solution as a Neuroprotective Against Ischemia/Reperfusion Injury. Preprints, 2018100105.

Iscan S, Eygi B. 2018. Neurologic and Renal Outcomes of Elective Proximal Aortic Repair and Current Cannulation Trends. Int J Clin Cardiol 5:128.

Iwama H, Akama Y, Tase C. 2000. Global brain ischemia produced by clamping left subclavian artery and bicarotid trunk in the rabbit. The American Journal of Emergency Medicine 18:31-35.

Kalogeris T, Baines CP, Krenz M, Korthuis RJ. 2012. Cell biology of ischemia/reperfusion injury. In International review of cell and molecular biology. Academic Press 298:229-317.

Kang SK, Kang MW, Rhee YJ, Kim CS, Jeon BH, Han SJ, et al. 2016. In vivo neuroprotective effect of histidine-tryptophan-ketoglutarate solution in an ischemia/reperfusion spinal cord injury animal model. The Korean Journal of Thoracic and Cardiovascular Surgery 49:232.

Karikari TK, Charway-Felli A, Höglund K, Blennow K, Zetterberg H. 2018. Commentary: global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Frontiers in Neurology 9:201.

Kurisu K, Abumiya T, Ito M, Gekka M, Osanai T, Shichinohe H, et al. 2016. Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion. Brain Res 1651:95-103.

Lautenschläger I, Pless-Petig G, Middel P, de Groot H, Rauen U, Stojanovic T. 2018. Cold Storage Injury to Rat Small-bowel Transplants—Beneficial Effect of a Modified HTK Solution. Transplantation 102:1666-1673.

Lazarewicz JW, Pluta R, Salinska E, Puka M. 1989. Beneficial effect of nimodipine on metabolic and functional disturbances in rabbit hippocampus following complete cerebral ischemia. Stroke 20:70-77.

Lee S, Huang CS, Kawamura T, Shigemura N, Billiar TR, Nakao A, et al. 2011. Histidine-tryptophan-ketoglutarateor Celsior: which is more suitable for cold preservation for cardiac grafts from older donors. AnnThorac Surg 91:755–763.

Lee S, Huang CS, Kawamura T, Shigemura N, Stolz DB, Billiar TR, et al. 2010. Superior myocardial preservation with HTK solution over Celsior in rat hearts with prolonged cold ischemia. Surgery 148:463–473.

Leshnower BG, Rangaraju S, Allen JW, Stringer AY, Gleason TG, Chen EP. 2019. Deep hypothermia with retrograde cerebral perfusion versus moderate hypothermia with antegrade cerebral perfusion for arch surgery. The Annals of Thoracic Surgery 107:1104-1110.

MacDougall G, Anderton RS, Mastaglia FL, Knuckey NW, Meloni BP. 2018. Mitochondria and neuroprotection in stroke: cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics. Neurobiol Dis 121:17-33.

Michel P, Vial R, Rodriguez C, Ferrera R. 2002. A comparative study of the most widely used solutions for cardiac graft preservation during hypothermia. The Journal of heart and lung transplantation 21:1030-1039.

Minami K, Omoto T, Böthig D, Tenderich G, Wlost S, Schütt U, et al. 2003. Creatine kinase and troponin after myocardial preservation using HTK solution (Custoidol) for clinical heart transplantation. The Journal of Heart and Lung Transplantation 22:192-194.

Okita Y, Miyata H, Motomura N, Takamoto S, & Organization T. J. C. S. D. A 2015. Study of brain protection during total arch replacement comparing antegrade cerebral perfusion versus hypothermic circulatory arrest, with or without retrograde cerebral perfusion: analysis based on the Japan Adult Cardiovascular Surgery Database. The Journal of Thoracic and Cardiovascular Surgery 149:65-73.

Prathanee S, Kuptanond C, Intanoo W, Wongbhudha C, Karunasumaeta C. 2015. Custodial-HTK Solution for Myocardial Protection in CABG Patients. J MedAssocThai 98:164-7.

Rao V, Liang P, Swerdlow N, Li C, Solomon Y, Wyers M, et al. 2020. Contemporary outcomes after carotid endarterectomy in high-risk anatomic and physiologic patients. Journal of Vascular Surgery 71:104-110.

Ringe B, Braun F, Moritz M, Zeldin G, Soriano H, Meyers W. 2005. Safety and efficacy of living donor liver preservation with HTK solution. In Transplantation proceedings 37:316-319.

Saitoh Y, Hashimoto M, Ku K, Kin S, Nosaka S, Masumura S, et al. 2000. Heartpreservation in HTK solution: role of coronary vasculature in recovery of cardiacfunction. Ann Thorac Surg 69:107-112.

Shintani N, Ishiyama T, Kotoda M, Asano N, Sessler DI, Matsukawa T. 2017. The effects of Y-27632 on pial microvessels during global brain ischemia and reperfusion in rabbits. BMC Anesthesiology 17:38.

Voigt MR, Ginger TD. 2013. Perspectives on abdominal organ preservation solutions: a comparative literature review. Progress in Transplantation 23:383-391.

Wei X, Hu CC, Zhang YL, Yao SL, Mao WK. 2016. Telmisartan reduced cerebral edema by inhibiting NLRP 3 inflammasome in mice with cold brain injury. Journal of Huazhong University of Science and Technology. Medical Sciences 36:576-583.

Yenari MA, Han HS. 2012. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267-278.



How to Cite

Oğuz, S., Aşgün, H. F., & Büyük, B. (2020). Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions. The Heart Surgery Forum, 23(4), E510-E516. https://doi.org/10.1532/hsf.3103