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."

Keywords: FGF21; RBM3; hypoxic/ischemic encephalopathy; space; targeted temperature management; therapeutic hypothermia.

FIG. 1.

The many layers of cerebroprotective cooling: the “Responsivity of Cold Stress Pathways” is an additional (new) concept for optimizing TH. Multiple interdependent factors affect the efficacy of neuroprotective TH in patients. Major variables include the duration of cooling, the device/instrumentation used to induce hypothermia, the time to reach target temperature, the depth of cooling, and the prevention of detrimental side effects. Purple text: the optimal hypothermia protocol(s) that increase tissue/plasma levels of neuroprotective CSHs remain to be elucidated. Nor is it known if TH is able to increase CSPs in the brain in human adults. Age-dependent and other patient-specific differences may alter (increase or decrease) the induction of CSHs/CSPs by TH, which in turn may influence neurological recovery after a CNS injury. Furthermore, additional work is needed to determine if CSHs/CSPs can be optimized (i.e., adjusted) using noncooling interventions such as pharmacological approaches. CNS, central nervous system; CSHs, cold stress hormones; CSPs, cold shock proteins; TH, therapeutic hypothermia.

FIG. 2.

Important (classic) mechanisms of neuroprotective hypothermia and potential side effects of total body cooling. Upper-left/white text: a broad group of neuroprotective mechanisms mediate neuroprotection by cooling in the CNS. Bottom-left: the magnitude of induction of different neuroprotective mechanisms depends, in part, on the depth of cooling. Clinically, the temperature ranges are divided into mild, moderate, deep, and profound. Recently, the term UMH was introduced to include therapeutic temperatures ranging above >35°C and below <36°C. Bottom-right: total body cooling is a complex “drug” that affects almost every organ/tissue in the body. Maximizing the clinical benefits of cerebral cooling depends, in part, on monitoring/controlling adverse side effects of hypothermia, germane to functional changes in other organ systems, which may inadvertently pose a risk to patient survival and/or CNS recovery after an injury. UMH, Ultramild Hypothermia.

FIG. 3.

The complex interplay/release of cold stress hormones (FGF21, Irisin, and Metrnl) by thermogenesis-regulating organs after cold exposure and possible targeting to the brain. The diagram shows the major sources of key circulating CSHs. FGF21-regulated mechanisms are illustrated in white text. Irisin-regulated mechanisms are illustrated in yellow text. Metrnl-regulated mechanisms are illustrated in green text. Potential unknown intersections (?) of paracrine effects on target tissues are indicated. All known signaling links and molecular targets are supported by research articles cited in the primary text. ATF, activating transcription factor; BAT, brown adipose tissue; eIF2α, eukaryotic initiation factor 2-alpha; FGF21, fibroblast growth factor 21; Metrnl, Meteorin-like; PKA, protein kinase A; PPARα, peroxisome proliferator-activated receptor-alpha; RBM3, RNA binding motif 3; SAT, subcutaneous adipose tissue; UCP, uncoupling protein; WAT, white adipose tissue.

FIG. 4.

SHBG is a novel target of hypothermia with unknown function(s) postcooling in humans and in bears. Illustration shows protein targets that are similarly altered (increased or decreased) by cooling in juvenile hibernating bears (Welinder et al., 2016) versus adult human CA patients treated with TH and who had a good neurological outcome (Deng et al., 2018). In both studies, proteomic changes were detected by mass spectrometry of blood plasma, and SHBG levels were among the highest fold change (compared with respective controls) among the identified proteins. CA, cardiac arrest; SHBG, sex hormone binding globulin.

FIG. 5.

Evidence supporting either a direct neuroprotective or neurotoxic function of RBM3, CIRBP, or RTN3 in the brain. Literature on RBM3, CIRBP, and RTN3 was obtained via PubMed. All articles were screened via an initial abstract review. A secondary search via Google was done to identify any additional articles not referenced in PubMed. Studies using in vitro neuronal injury paradigms (cell lines or primary neurons) or in vivo brain injury/disease models were analyzed in-depth (i.e., if available). One article was in Chinese and converted to English using Google translate. Purely observational studies were identified and excluded. This figure incorporates studies that (1) overexpressed, (2) knocked down, or (3) incubated neuronal cells/tissues with a recombinant CSP (or any combination of the three) in vitro and/or in vivo, to generate a direct conclusion germane to a given CSP protective versus detrimental function(s). For the purpose of this review, we did not rate the “quality of the evidence” but noted that the scientific rigor varied considerably across studies. Top: findings were organized into “Battlefield Boxes,” which summarize the opposing sides of evidence that support either neuroprotective (blue region) or neurotoxic (red region) roles of CSPs. White dots indicate individual studies and each is aligned with the year of publication. Stacked dots indicate multiple studies published in the same year. A total “Score” was given (large white numbers on the right side of the squares), which is the sum of all studies that supported either protective or detrimental functions of each CSP. The literature epoch spans approximately two decades from 2002 to 2019. Bottom: an overview of the diverse cell signaling mechanisms reported to mediate neuroprotective versus neurotoxic effects of CSPs. The proposed mechanisms are based on the experimental data presented by articles shown in the Battlefield Boxes. All articles are cited in the main text, and also listed here in order of publication date. RBM3: Kita et al., Chip et al., Zhu et al., Peretti et al., Yang et al., Bastide et al., Zhuang et al., Yang et al., Xia et al. CIRBP: Saito et al., Li et al., Rajayer et al., Zhou et al., Liu et al., Zhang et al., Li et al., Zhang et al., Wang et al., Chen et al. RTN3: Hu et al., Shi et al., Shi et al., Chen et al., Shi et al., Teng and Tang, Araki et al., Shi et al., Sharoar et al., Bastide et al., Zou et al. CIRBP, Cold inducible RNA binding protein; RTN3, reticulin-3.

FIG. 6.

Medical conditions amenable to a “Hypothermia in a Syringe” strategy. Hypothermia in a Syringe is the theoretical concept that CSH/CSP levels can be (collectively) pharmacologically manipulated in normothermic or hypothermic patients to mimic (or augment) aspects of beneficial cold response physiology and cell signaling cascades. The illustration shows examples of major research fields (individual fruits), and medical conditions relevant to each (white text), which may represent low-hanging fruit for clinical translation. Prioritization of the “lowest hanging fruit” is left to the reader to interpret given that the metaphor is context dependent (e.g., the lowest hanging fruit might represent a condition most applicable to a therapy, or alternatively a condition via which a therapy is able to translate into the clinic the fastest).

FIG. 7.

Theoretical multiorgan benefits of Hypothermia in a Syringe in the setting of long-duration spaceflight. Astronauts exposed chronically to microgravity and increased levels of radiation have evidence of cumulative tissue damage, and show marked changes in baseline physiology that may predispose organs such as the brain to a state of enhanced vulnerability. The utility of protective cooling in astronauts is a well-recognized potential therapy to prevent tissue damage during long-duration spaceflight. However, the technology involved in the implementation of cooling systems and protocols able to safely maintain a state of suspended animation in humans is incomplete. Moreover, adopting standard hypothermia equipment (e.g., the artic sun system) for a shuttle or medical module, and used for acute cooling in the event of an accidental injury (e.g., traumatic brain injury), will require overcoming design and training challenges to ensure patient safety in microgravity. Thus, in the relative near term, developing IV-based therapeutics that quickly and easily activate neuroprotective cold responsive signaling pathways in astronauts, and without the need for cooling, may represent a technically simpler approach for space travel (although not necessarily a replacement for the latter). Germane to that logic, key CSPs discussed in this review show promise in reversing physiological changes and cellular pathologies that appear to be associated with spaceflight. For instance, RBM3 (1) prevents cognitive impairment in models of Alzheimer's disease, (2) protects against muscle atrophy, and (3) may decrease bone loss. CIRBP promotes DNA repair mechanisms after ionizing radiation (but this effect is yet to be tested in neurons of the brain). Finally, RTN3 decreases Aβ plaque burden in the brain. CSHs may also mediate beneficial and/or detrimental effects on altered physiology in astronauts. In particular, Metrnl is associated with pathways involved in muscle strength and anti-inflammatory signaling in WAT. In addition, higher SHBG plasma levels are associated with increased white matter in men, but whether that relationship is causative or correlative remains unclear, and also needs to be investigated in women. Finally, FGF21 may activate neuroprotective pathways in the brain, or conversely, further promote a detrimental “space fever” phenotype in astronauts by activating heat-generating thermogenesis mechanisms in BAT. Aβ, beta-amyloid; IV, intravenous.