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

Travis C Jackson,Patrick M Kochanek

doi:10.1089/ther.2019.0001

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.”

Highlights

The Egyptians recognized the medical utility of hypothermia 5000 years ago, local head cooling for traumatic brain injury (TBI) was used by Phelps in the late 1800s, and total body cooling for the treatment of head injury was first applied in 1938 by the neurosurgeon Temple Fay (Phelps, 1897; Wang et al, 2006; Karnatovskaia et al, 2014)
More recently (2015), we introduced the term Ultramild Hypothermia (UMH) for temperatures >35°C and p36°C based on evidence that (1) 36°C versus 37°C induced a bona fide intracellular cold shock response in cultured primary neurons in vitro ( Jackson et al, 2015), (2) Berntman et al (1981) showed that 36°C versus 37°C improved biochemical markers of brain damage after hypoxic/ischemic injury in adult rats, and (3) as discussed earlier, rigorous clamping of patients at 36°C confers benefit after cardiac arrest, an effect that may not represent prevention of fever (Nielsen et al, 2013)
In this review we have focused on the potential role of cold shock proteins (CSPs)/cold stress hormones (CSHs) in acute brain injury and chronic neurodegeneration, it is important to briefly summarize the classic neuroprotective mechanisms induced by hypothermia, to provide a base of understanding, and to clarify the integration of novel concepts posed here into the full scheme of hypothermic neuroprotection (Fig. 2, upper left)

Summary

Introduction

The Egyptians recognized the medical utility of hypothermia 5000 years ago, local head cooling for traumatic brain injury (TBI) was used by Phelps in the late 1800s, and total body cooling for the treatment of head injury was first applied in 1938 by the neurosurgeon Temple Fay (Phelps, 1897; Wang et al, 2006; Karnatovskaia et al, 2014). To begin to link those traditional findings to the concept of ‘‘Responsivity of Cold Stress Pathways,’’ to TH, we review four cold stress hormones (CSHs) and three cold shock proteins (CSPs), discuss their prominent role in the developing brain, and speculate on the manner in which modulating their levels may be an important step in optimizing TH-mediated neuroprotection in adult humans to compensate for a limited Responsivity of Cold Stress Pathways. To emphasize its potential applications in settings well beyond existent medical needs, and to envision the risks and benefits of this strategy under injury conditions that would affect the entire organism (brain and body), we close by discussing the futuristic possibilities of using Hypothermia in a Syringe to target cellular pathways that defend against the detrimental effects associated with long-duration spaceflight

Classic Mechanisms Mediating Neuroprotective Hypothermia

Sex hormone binding globulin

Cold inducible RNA binding protein

Concluding Remarks

Findings

Author Disclosure Statement