Download PDF
J Neurol Surg B Skull Base 2022; 83(02): 203-209
DOI: 10.1055/s-0040-1721818
Original Article

Novel Focal Therapeutic Hypothermia Device for Treatment of Acute Neurologic Injury: Large Animal Safety and Efficacy Trial

Lucas P. Carlstrom
1   Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
,
Avital Perry
1   Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
,
Christopher S. Graffeo
1   Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
,
Daying Dai
2   Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States
,
Yong H. Ding
2   Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States
,
Daniel R. Jakaitis
2   Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States
,
Aiming Lu
3   Department of Medical Physics, Mayo Clinic, Rochester, Minnesota, United States
,
Seth Rodgers
4   NeuroSave Inc., San Francisco, California, United States
,
Thomas Kreck
4   NeuroSave Inc., San Francisco, California, United States
,
Kelly Hoofer
4   NeuroSave Inc., San Francisco, California, United States
,
Krzysztof R. Gorny
3   Department of Medical Physics, Mayo Clinic, Rochester, Minnesota, United States
,
Ramanathan Kadirvel
2   Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States
,
David F. Kallmes
2   Department of Radiology, Mayo Clinic, Rochester, Minnesota, United States
› Author Affiliations Funding The study was funded by Mayo Clinic Radiology Research Committee.
› Further Information
    Permissions and Reprints

Abstract

Objective Therapeutic hypothermia is a potentially powerful and controversial clinical tool for neuroprotection following acute neurologic pathology, particularly vascular injury. Indeed, therapeutic hypothermia remains a standard of care for postcardiac arrest ischemia and acute neonatal hypoxic-ischemic encephalopathy, improving both survival and outcomes. Although therapeutic hypothermia remains promising for cellular and systems-based neuronal protection in other neurologic injury states, the systemic side effects have limited clinical utility, confounded analysis of potential neurologic benefits, and precluded the completion of meaningful clinical trials.

Methods To address such limitations, we developed and tested a novel, minimally invasive, neurocritical care device that employs continuous circulation of cold saline through the pharyngeal region to deliver focal cerebrovascular cooling. We conducted a preclinical safety and efficacy trial in six adult porcine animals to assess the validity and functionality of the NeuroSave device, and assess cooling potential following middle cerebral artery occlusion (n = 2).

Results NeuroSave consistently lowered brain parenchymal temperature by a median of 9°C relative to core temperature within 60 minutes of initiation, including in ischemic cerebral parenchyma. The core body temperature experienced a maximal reduction of 2°C, or 5% of body temperature, with no associated adverse effects identified.

Conclusion The present study uses a large animal preclinical model to demonstrate the safety and efficacy of a novel, noninvasive device for the induction of robust and systemically safe hypothermia within the brain.

Keywords

therapeutic hypothermia - device - development - central nervous system cooling

Authors' Contributions

L.P.C., A.P., C.S.G., D.D., Y.H.D., D.R.J., A.L., K.R.G., R.K., and D.F.K. all performed direct procedures related to device set up and use, formal data collection, and/or histopathologic assessment. L.P.C., A.P., and C.S.G. wrote the manuscript. R.K. and D.F.K. supervised the project and edited the manuscript. S.R., T.K., and K.H. provided quality control to ensure the device was set up properly. All authors provided final approval for submission.




Publication History

Received: 25 March 2020

Accepted: 11 September 2020

Article published online:
08 March 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 69 (01) CD003311
    PubMedGoogle Scholar
  • 2 Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 2012; 13 (04) 267-278
    CrossrefPubMedGoogle Scholar
  • 3 Lewis SR, Evans DJ, Butler AR, Schofield-Robinson OJ, Alderson P. Hypothermia for traumatic brain injury. Cochrane Database Syst Rev 2017; 9: CD001048
    PubMedGoogle Scholar
  • 4 Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma 2008; 25 (01) 62-71
    CrossrefPubMedGoogle Scholar
  • 5 Crompton EM, Lubomirova I, Cotlarciuc I, Han TS, Sharma SD, Sharma P. Meta-analysis of therapeutic hypothermia for traumatic brain injury in adult and pediatric patients. Crit Care Med 2017; 45 (04) 575-583
    CrossrefPubMedGoogle Scholar
  • 6 Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy - where to from here?. Front Neurol 2015; 6: 198
    CrossrefPubMedGoogle Scholar
  • 7 Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 1996; 53 (04) 309-315
    CrossrefPubMedGoogle Scholar
  • 8 Wijdicks EF, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clin Proc 1998; 73 (09) 829-836
    CrossrefPubMedGoogle Scholar
  • 9 Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29 (12) 2461-2466
    CrossrefPubMedGoogle Scholar
  • 10 Krieger DW, De Georgia MA, Abou-Chebl A. et al. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 2001; 32 (08) 1847-1854
    CrossrefPubMedGoogle Scholar
  • 11 Horn CM, Sun C-HJ, Nogueira RG. et al. Endovascular Reperfusion and Cooling in Cerebral Acute Ischemia (ReCCLAIM I). J Neurointerv Surg 2014; 6 (02) 91-95
    CrossrefPubMedGoogle Scholar
  • 12 Reglodi D, Somogyvari-Vigh A, Maderdrut JL, Vigh S, Arimura A. Postischemic spontaneous hyperthermia and its effects in middle cerebral artery occlusion in the rat. Exp Neurol 2000; 163 (02) 399-407
    CrossrefPubMedGoogle Scholar
  • 13 Arikan F, Martínez-Valverde T, Sánchez-Guerrero Á. et al. Malignant infarction of the middle cerebral artery in a porcine model. A pilot study. PLoS One 2017; 12 (02) e0172637
    CrossrefPubMedGoogle Scholar
  • 14 Imai H, Konno K, Nakamura M. et al. A new model of focal cerebral ischemia in the miniature pig. J Neurosurg 2006; 104 (2, Suppl): 123-132
    PubMedGoogle Scholar
  • 15 Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009; 37 (7, Suppl): S186-S202
    CrossrefPubMedGoogle Scholar
  • 16 Zhao Q-J, Zhang X-G, Wang L-X. Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. J Crit Care 2011; 26 (03) 311-315
    CrossrefPubMedGoogle Scholar
  • 17 Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in mammalian central nervous system. J Cereb Blood Flow Metab 2003; 23 (05) 513-530
    CrossrefPubMedGoogle Scholar
  • 18 Lasarzik I, Winkelheide U, Thal SC. et al. Mild hypothermia has no long-term impact on postischemic neurogenesis in rats. Anesth Analg 2009; 109 (05) 1632-1639
    CrossrefPubMedGoogle Scholar
  • 19 Dietrich WD, Busto R, Halley M, Valdes I. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990; 49 (05) 486-497
    CrossrefPubMedGoogle Scholar
  • 20 Gupta R, Connolly ES, Mayer S, Elkind MS. Hemicraniectomy for massive middle cerebral artery territory infarction: a systematic review. Stroke 2004; 35 (02) 539-543
    CrossrefPubMedGoogle Scholar
  • 21 Jeong H-Y, Chang J-Y, Yum KS. et al. Extended use of hypothermia in elderly patients with malignant cerebral edema as an alternative to hemicraniectomy. J Stroke 2016; 18 (03) 337-343
    CrossrefPubMedGoogle Scholar
  • 22 Guluma KZ, Oh H, Yu S-W, Meyer BC, Rapp K, Lyden PD. Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial. Neurocrit Care 2008; 8 (01) 42-47
    CrossrefPubMedGoogle Scholar
  • 23 Georgiadis D, Schwarz S, Kollmar R, Schwab S. Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke 2001; 32 (11) 2550-2553
    CrossrefPubMedGoogle Scholar
  • 24 De Georgia MA, Krieger DW, Abou-Chebl A. et al. Cooling for acute ischemic brain damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 2004; 63 (02) 312-317
    CrossrefPubMedGoogle Scholar
  • 25 Bower RS, Sunnarborg R, Rabinstein AA, Wijdicks EF. Paroxysmal sympathetic hyperactivity after traumatic brain injury. Neurocrit Care 2010; 13 (02) 233-234
    CrossrefPubMedGoogle Scholar
  • 26 Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke 1998; 29 (02) 529-534
    CrossrefPubMedGoogle Scholar
  • 27 Cooper DJ, Nichol AD, Bailey M. et al; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial. JAMA 2018; 320 (21) 2211-2220
    CrossrefPubMedGoogle Scholar
  • 28 Skitzki JJ, Repasky EA, Evans SS. Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs 2009; 10 (06) 550-558
    PubMedGoogle Scholar
  • 29 Dewhirst MW, Vujaskovic Z, Jones E, Thrall D. Re-setting the biologic rationale for thermal therapy. Int J Hyperthermia 2005; 21 (08) 779-790
    CrossrefPubMedGoogle Scholar
  • 30 Hong JM, Lee JS, Song H-J, Jeong HS, Choi HA, Lee K. Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke 2014; 45 (01) 134-140
    CrossrefPubMedGoogle Scholar