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Intra-Arterial Selective Cooling in Acute Systemic Stroke

By Currents Editor posted 05-07-2020 11:06

Intra-Arterial Selective Cooling in Acute Systemic Stroke
By Francisco Gomez, MD1; Ivo Bach, MD2; and Fawaz Al-Mufti, MD3

Department of Neurology, University of Pennsylvania
2 Department of Neurology, Rutgers - New Jersey Medical School
Department of Neurology and Neurosurgery, Westchester Medical Center at New York Medical College

The authors have no actual or potential conflict of interest in relation to the topics discussed in this column. This article may discuss non-FDA approved devices and “off-label” uses. The NCS and Currents do not endorse any particular device.

Thrombectomy and Cooling
Thrombectomy and thrombolysis have proven effective in the treatment of stroke; however, strides remain to be made to promote tisular reperfusion itself. Various methods of neuroprotection have been posed as a possible strategies to minimize stroke burden in conjunction with recanalization. One of the proposed methods has been therapeutic hypothermia. Whole-body cooling has been studied extensively, showing promise in preclinical studies, as well as proven feasible. However, an outsized impact on outcomes remains to be found, most recently noted on the multicenter, randomized EUROHYP-1 trial.

Additionally, whole-body cooling has several drawbacks, including shivering and elevated intracranial pressure, which may necessitate additional sedation, increased risk of pneumonia, and electrolyte and metabolic derangements. Furthermore, whole-body cooling is slower to reach goal temperature, as compared to a local infusion that can cool tissue in less than 10 minutes. Given metabolic derangements and secondary stroke damage have been shown to be time-sensitive, a more rapid onset technique could prove advantageous. Thus, targeted cooling may prove more effective without the side effects and treatment complexity associated with whole-body cooling.

Intra-Arterial Selective Cooling
A proposed method for more targeted therapy is intra-arterial cooling or Local Endovascular Infusion (LEVI). LEVI comprises cooled saline infusion through the same access obtained for thrombectomy, with the goal of causing local hypothermia at the site of ischemic injury. The procedure can be performed prior to recanalization, after or both.


Proposed Mechanisms of Action of Selective Cooling
LEVI has shown promise in both animal models and patients, with various theorized mechanisms, such as washout of deleterious metabolites, inhibition of cortical spreading depolarizations and various effects on local inflammation. This technique may decrease intracellular adhesion molecule-1 expression, thus limiting leukocyte infiltration and possibly decreasing the production of reactive oxygen species and pro-inflammatory cytokines. Animal studies have shown upregulation of brain-derived neurotrophic factor and splenic interleukin 10, which may be immunomodulatory in this case. LEVI may also aid in preserving blood-brain barrier integrity by decreasing matrix metallopeptidase 9 and aquaporin-4 expression thus decreasing local edema. It is also postulated that metabolites, such as lactate, carbon dioxide and prostaglandins, are responsible for deleterious vasodilation once reperfusion is achieved and that washout of these moieties may decrease reperfusion injury. This effect was also observed with warm saline infusion, further suggesting plain irrigation may be of benefit.

Current Studies and Techniques
In one study enrolling 113 participants, 45 of which underwent short-duration intra-arterial selective cooling infusion. Once the clot was traversed with the microcatheter, an infusion of 10ml/min 0.9% saline at 4°C was applied for 5 minutes. Following thrombectomy, the infusion rate was increased to 30ml/min and continued for an additional 10 minutes. A statistically significant decrease in final infarct volume averaging 19.1ml was observed in the intervention arm; however, there was no significant difference in 90-day outcomes or return to independence. In the end, it was concluded that LEVI was both clinically feasible and safe.

Future Directions
Overall, there seems to be compelling evidence that intra-arterial cooling prior to and possibly after recanalization is safe and poses little logistical challenge in execution, as well as decreasing final injury volume. LEVI also appears to be a promising avenue for trials involving other neuroprotectants via the same route as the cooled saline. Magnesium sulfate, albumin, erythropoietin and NMDA receptor antagonists have been trialed in this fashion, significantly reducing the infarct volumes in preclinical studies.

  • Dumitrascu, O. M., Lamb, J., & Lyden, P. D. (2016). Still cooling after all these years: Meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke. Journal of Cerebral Blood Flow & Metabolism, 36(7), 1157–1164.
  • Duan H, Huber M, Ding JN, Huber C, Geng X. Local endovascular infusion and hypothermia in stroke therapy: A systematic review. Brain Circ. 2019;5(2):68-73.
  • Wu C, Zhao W, An H, et al. Safety, feasibility, and potential efficacy of intraarterial selective cooling infusion for stroke patients treated with mechanical thrombectomy. J Cereb Blood Flow Metab. 2018;38(12):2251-2260.
  • Song W, Wu YM, Ji Z, Ji YB, Wang SN, Pan SY. Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion. Neurol Sci. 2013;34(4):479-86.
  • Duan Y, Wu D, Huber M, et al. New Endovascular Approach for Hypothermia With Intrajugular Cooling and Neuroprotective Effect in Ischemic Stroke. Stroke. 2020;51(2):628-636.
  • Geurts, M., Petersson, J., Brizzi, M., Olsson-Hau, S., Luijckx, G.-J., Algra, A., … van der Worp, H. B. (2016). COOLIST (Cooling for Ischemic Stroke Trial). Stroke, 48(1), 219–221.doi:10.1161/strokeaha.116.014757
  • Corey, S., Abraham, D. I., Kaneko, Y., Lee, J.-Y., & Borlongan, C. V. (2019). Selective endovascular cooling for stroke entails brain-derived neurotrophic factor and splenic IL-10 modulation. Brain Research, 146380.doi:10.1016/j.brainres.2019.146380
  • CORDIS, EUROHYP-1, European multicentre, randomised, phase III clinical trial of hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke. Retrieved March 10, 2020

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