A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis

Abstract

Three decades of animal studies have reproducibly shown that hypothermia is profoundly cerebroprotective during or after a central nervous system (CNS) insult. The success of hypothermia in preclinical acute brain injury has not only fostered continued interest in research on the classic secondary injury mechanisms that are prevented or blunted by hypothermia but has also sparked a surge of new interest in elucidating beneficial signaling molecules that are increased by cooling. Ironically, while research into cold-induced neuroprotection is enjoying newfound interest in chronic neurodegenerative disease, conversely, the scope of the utility of therapeutic hypothermia (TH) across the field of acute brain injury is somewhat controversial and remains to be fully defined. This has led to the era of Targeted Temperature Management, which emphasizes a wider range of temperatures (33–36°C) showing benefit in acute brain injury. In this comprehensive review, we focus on our current understandings of the novel neuroprotective mechanisms activated by TH, and discuss the critical importance of developmental age germane to its clinical efficacy. We review emerging data on four cold stress hormones and three cold shock proteins that have generated new interest in hypothermia in the field of CNS injury, to create a framework for new frontiers in TH research. We make the case that further elucidation of novel cold responsive pathways might lead to major breakthroughs in the treatment of acute brain injury, chronic neurological diseases, and have broad potential implications for medicines of the distant future, including scenarios such as the prevention of adverse effects of long-duration spaceflight, among others. Finally, we introduce several new phrases that readily summarize the essence of the major concepts outlined by this review—namely, Ultramild Hypothermia, the “Responsivity of Cold Stress Pathways,” and “Hypothermia in a Syringe.”

Neurological outcome in patients after successful resuscitation in out-of-hospital settings

“…Between patients with good and adverse neurological outcome, we did not observe any significant differences in the achieved target temperatures 32-34°C. This finding is in agreement with a large study demonstrating that therapeutic normothermia or temperature control at 36°C may be equally effective as hypothermia at 32-34°C in long-term regarding neurological outcomes in brain injury [3,23]. On the other hand, the interaction of different variables such as age and/or other unidentified processes determine the magnitude by which hypothermia increases the activation of cold stress molecules in biological systems, which alter brain physiology during therapeutic hypothermia.…”

“…On the other hand, the interaction of different variables such as age and/or other unidentified processes determine the magnitude by which hypothermia increases the activation of cold stress molecules in biological systems, which alter brain physiology during therapeutic hypothermia. Therapeutic hypothermia is robustly influenced by age and is beneficial more in younger patients in addition to other therapeutic measures in the ICU [23].…”

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

“…Controlled cooling is an integral part of many clinical procedures, principally aiming to reduce the cellular metabolic needs of organs and tissues to prevent ischemic cell death when blood supply is interrupted. Whilst the benefit of reduced metabolic rates for cell survival has long been appreciated, the activation of specific pathways has only recently been recognized as a critical contributor to the cell preservation effect afforded by low temperatures (Bastide et al, 2017;Peretti et al, 2015;Ou et al, 2018) (Jackson & Kochanek, 2019). Unlike the metabolic rate that gradually reduces as temperature decreases, we show that the activation of pathways in response to cold is more complex.…”

“…1-2) and is finely balanced between beneficial and detrimental outcomes (Hattori et al, 2017), limiting its therapeutic scope. The importance of controlled cooling as a clinical tool (Peretti et al, 2015;Gordon, 2001;Bastide et al, 2017;Kutcher et al, 2016) and its potential to provide solutions to overcome the physiological challenges of long duration space flight (Nordeen & Martin, 2019;Choukèr et al, 2019;Jackson & Kochanek, 2019), expose the need to understand the cellular response to cooling at the molecular level. Elucidating these processes will ultimately provide solutions to pharmacologically activate beneficial pathways without the need for cooling and inactivate detrimental pathways to expand the remit of controlled cooling for medical applications.…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…136,137 Klotho regulates phosphorus and calcium homeostasis 5,6,18,23,138 and functions as an obligatory co-receptor that binds and activates its related endocrine fibroblast growth factor (FGF) receptors (FGFRs) to potentiate its biological activities. 5,6,23,102,[139][140][141][142][143][144][145][146] FGFs are exemplary pleiotropic hormones that play numerous roles in cellular and metabolic homeostasis. 5,6,137,141,[144][145][146][147][148] In particular, FGF23 is a bone-derived hormone that in conjunction with Klotho acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. 5,6,14,23,102,136,138,145,148,149 Vitamin D regulates epigenetic mechanisms that maintain the transcription of its target genes in regulatory networks, including the expression of Klotho and nuclear factor-erythroid-2related factor 2 (Nrf2) to carry out many of its homoeostatic functions.…”