(March, 2025) In the early 80’s, W. Dalton Dietrich, PhD, was recruited to the Department of Neurology, University of Miami to collaborate with colleagues in the internationally recognized Cerebrovascular Disease Research Center (CVDRC). One early task was to develop morphological approaches to quantitatively assess pathological damage in models of cerebral ischemia and stroke. An observation from evaluating hundreds of histological slides that would impact his research programs for decades was that the cerebral ischemia models resulted in variable degrees of hippocampal neuronal damage, a structure important in memory and learning. Studies were designed to determine the reasons for these neuropathological inconsistencies which presented major challenges for investigating injury mechanisms and the testing of therapeutic approaches.
Dietrich and CVDRC colleagues investigated multiple factors for this reproducibility issue including ischemic severity, metabolic and electrophysiological differences, but could not identify a reasonable explanation. An important clue came from the early cardiac bypass clinical literature showing that rather large reductions in whole body temperature (profound hypothermia) protected various organ systems during some surgical procedures. This awareness of the literature ultimately led to studies that demonstrated inconsistencies between systemic temperatures and ischemic brain temperatures where variable degrees of uncontrolled mild hypothermia were recorded. “I remember searching the literature for data on human brain temperature measurements and found limited information on the subject”, said Dietrich. This observation led to the hypothesis that in contrast to profound hypothermia, rather mild reductions in brain temperature between 2 or 3oC were enough to protect the brain after an ischemic insult. “These were exciting times in the CVDRC where our research group including Drs. Myron Ginsberg, Peritz Scheinberg, Mordecai Globus, and Raul Busto began evaluating the effects of intraischemic and post-ischemic mild hypothermia as a critical step for the possible translation of this treatment to patients suffering from brain injury,” said Dietrich.
New experiments were designed where brain temperatures were maintained at precise temperature levels during and after the ischemic insult to determine temperature-dependent effects on histopathological outcome. Results showed that while relatively small reductions in brain temperature protected against neuronal damage, mild elevations in brain temperature (hyperthermia) that occur during periods of fever increased ischemic damage. Subsequent publications and presentations at national and international meetings helped spread the word about these exciting findings coming out of Miami with groups conducting their own temperature studies. The good news was that our major conclusions were replicated by many laboratories and Therapeutic Hypothermia (TH) is today considered one of the most powerful neuroprotective strategies for protecting the brain and spinal cord after injury. The University of Miami became one of the premier institutes for medical research and training in TH and targeted temperature management (TTM) for many years to come.
An Explosion in the Field
Based on the Miami findings, there was an explosion of experimental studies and clinical research using TH in out-of-hospital cardiac arrest patients, cerebral ischemia, traumatic brain and spinal injury. Two major TH clinical studies published in 2002 reported for the first time the beneficial outcomes in cardiac arrest patients showing that the cooling improved outcomes and decreased mortality rates. In infants suffering from neonatal hypoxic-ischemic encephalopathy, cooling studies were also initiated that also demonstrated significant benefits. “Laboratories started measuring brain temperatures, inducing periods of TH or inhibiting periods of hyperthermia leading to the new field of TTM for different neurological patient populations,” said Dr. Dietrich.
Attention was also directed at clarifying the cellular and molecular injury mechanisms underlying cooling-induced protection. Several studies reported that small temperature variations affected multiple secondary injury pathways felt to be involved in the pathogenesis of injury-induced damage. Indeed, the ability of mild hypothermia to impact multiple injury pathways is felt to underlie its powerful neuroprotective effect on ischemic damage said Dietrich, now Professor of Neurological Surgery and Scientific Director of The Miami Project to Cure Paralysis at the Miller School of Medicine. Today, many patients undergo TH or TTM procedures to reduce secondary injury mechanisms or protect against unwanted periods of brain hyperthermia. Because of the clinical issue of patient heterogeneity and the goal of providing personalized medicine, research programs are currently focused on developing surrogate biomarkers to predict which patients would best benefit from TH and TTM by selecting specific cooling levels and durations to maximize benefits.
The School of Medicine’s Role Today
Today, hundreds of manuscripts are published each year on the benefits and limitations of TH and TTM in clinical settings. Current clinical studies at the MSOM led by Dr. Allan Levi, Professor and Chair, Department of Neurological Surgery, include a 6-site multicenter TH trial in acutely injured SCI patients where limited treatments are available to improve functional outcomes. Other studies led by Dr. Suhrud Rajguru and colleagues, Departments of Biomedical Engineering and Otolaryngology are assessing the beneficial effects of local ear cooling during cochlear implantation procedures or noise-induced hearing loss to reduce damage to inner ear hair cells important for hearing.
In terms of discovery research, Dr. Dietrich and colleagues continue to study the pathological consequences of brain and SCI using the next generation of technological approaches. A current study by Drs. Nadine Kerr, Helen M. Bramlett, Jae Lee and Dietrich is using next generation single cell genomic analyses to determine how TH affects various subtypes of neurons, glia, endothelial, and inflammatory cells after ischemic and traumatic injury. Drs. Dietrich and Bramlett are also working with Drs. Sylvia Daunert and Sapna Deo in the Department of Biochemistry & Molecular Biology to develop the first nanodrug that can be intranasally administered to rapidly induce mild hypothermia on the way to the hospital.
Over a 10-year period Drs. Dietrich and Bramlett hosted the UM Annual “Chilling at the Beach” scientific conferences on TH and TTM where invited experts gathered in Miami to debate the use of these experimental strategies in respective patient populations. International Hypothermia Symposia were hosted in Tokyo Japan, Lund Sweden, Eindhoven Netherlands, Philadelphia, and Miami to advance new technologies to effectively cool patients in a controlled and safe manner. In 2011, sustained interest led to the creation of a new Journal entitled Therapeutic Hypothermia and Temperature Management for publishing new articles and state-of-the-art reviews. Faculty and trainees continue to conduct research on the fundamental question of how small variations in neural temperatures can improve or worsen outcomes while bringing together researchers from many countries to work on related projects.
Looking back over the last 40 years there are many fond memories and lessons learned from working with the hundreds of individuals that were instrumental in investigating this scientifically interesting and clinically important topic. Today, the TH field remains highly relevant and stands as a success story for the translation of a pre-clinical therapy to the clinic. “As research questions continue to evolve and technologies become more sophisticated, researchers remain excited about the future uses of cooling and temperature management for protecting and repairing the nervous system from human diseases and other disorders,” said Dr. Dietrich.
By: Emma Yasinski more