Cool It: Miller School Plays Significant Role in Therapeutic Hypothermia
Article Summary
- Dr. W. Dalton Dietrich and Miller School colleagues are trailblazers in the study of therapeutic hypothermia.
- In the field’s nascent era, Dr. Dietrich and colleagues found that cooling the body protected certain organ systems.
- They hypothesized that small reductions in body temperature would protect against ischemic insult.
Podcast: Does TBI Lead to Dementia? Can Therapeutic Hypothermia Help?
In 1981, W. Dalton Dietrich, Ph.D., came to the University of Miami Miller School of Medicine’s Department of Neurology to collaborate with colleagues in the 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.
Hypothesizing About Brain Temperature
After evaluating hundreds of histological slides that would impact his research programs for decades, Dr. Dietrich observed that the ischemia models resulted in variable degrees of hippocampal neuronal damage. He designed studies to determine the reasons for these neuropathological inconsistencies, which presented challenges for investigating injury mechanisms and testing therapies. Dr. Dietrich and colleagues investigated factors including ischemic severity and metabolic and electrophysiological differences. But they couldn’t identify obvious reasons for model variability.
Clinical literature revealed an important clue. Large reductions in whole-body temperature (profound hypothermia) protected organ systems during some surgical procedures. That discovery led to investigations that demonstrated inconsistent relationships between controlled systemic temperatures and brain temperatures that involved different degrees of uncontrolled, mild hypothermia.
“I remember searching the literature for any data on human brain temperature measurements and found limited information on the subject,” said Dr. Dietrich, scientific director of The Miami Project to Cure Paralysis and professor of neurological surgery, neurology, biomedical engineering and cell biology at the Miller School.
He hypothesized that two- to three-degree reductions in brain temperature were enough to protect the brain after an ischemic insult.
“These were exciting times in the CVDRC. Our research group, including Drs. Ginsberg, Scheinberg, Globus and Busto, began evaluating the effects of post-ischemic mild hypothermia as a critical step in moving this therapy to patients suffering from brain injury,” Dr. Dietrich said.
The team maintained precise brain temperature levels during and after ischemic insult to determine temperature-dependent effects on outcomes. The researchers learned relatively small reductions in brain temperature protected against neuronal damage, but mild elevations in brain temperature (hyperthermia) that may occur during periods of fever increased ischemic damage.
Word started getting around about these significant findings coming out of Miami.
“The good news was that our major conclusions were replicated by many laboratories and therapeutic hypothermia is today considered one of the most powerful neuroprotective strategies for protecting the brain and spinal cord from injury,” Dr. Dietrich said. “The University of Miami became one of the premiere institutes for medical research and training in therapeutic hypothermia and targeted temperature management.”
An Explosion in the Therapeutic Hypothermia Field
Experimental studies and clinical research using therapeutic hypothermia in out-of-hospital cardiac arrest patients and acute stroke followed. Two major clinical studies published in 2002 reported beneficial outcomes in cardiac arrest patients. Cooling improved outcomes and decreased mortality rates.
In infants suffering from neonatal hypoxic-ischemic encephalopathy, cooling studies also appeared beneficial.
“Laboratories all over the world started measuring brain temperatures, inducing periods of therapeutic hypothermia or inhibiting periods of hyperthermia, leading to the new field of targeted temperature management for cardiac arrest, acute ischemic stroke, seizures, and traumatic brain, concussion and spinal cord injury,” said Dr. Dietrich.
Researchers also clarified the cellular and molecular injury mechanisms underlying cooling-induced protection. Small temperature variations, they found, affected multiple, secondary injury pathways believed to be involved in the pathogenesis of injury-induced damage. Indeed, the ability of mild hypothermia to impact multiple injury pathways may be key to its powerful neuroprotective effect on ischemic damage, said Dr. Dietrich.
Today, it’s common for patients to undergo therapeutic hypothermia or targeted temperature management procedures to reduce secondary injury mechanisms or protect against unwanted periods of brain hyperthermia. With the ascent of personalized medicine, research is developing surrogate fluid and imaging biomarkers to predict which patients would benefit from targeted hypothermia and targeted temperature management by selecting specific cooling levels and durations to maximize benefits.
The Miller School and Contemporary Therapeutic Hypothermia
Hundreds of manuscripts are published each year on the benefits and limitations of therapeutic hypothermia and targeted temperature management in clinical settings. The Miller School, led by Allan Levi, M.D., Ph.D., the Miller School’s professor and chair of the Department of Neurological Surgery, is involved in a six-site, multicenter therapeutic hypothermia trial for patients with acute spinal cord injuries and no viable treatments.
Studies led by biomedical engineering and otolaryngology professor Suhrud Rajguru, Ph.D., and researchers in the Department of Otolaryngology are assessing the effects of local ear cooling during cochlear implantation to reduce damage to inner ear hair cells. In the areas of clinical stroke, cooling strategies are being combined with intravascular approaches like clot thrombolysis and thrombectomy to promote cerebral reperfusion and protect ischemic areas vulnerable to injury.
Dr. Dietrich and colleagues use contemporary technology to study the pathological consequences of brain and spinal cord injury. A current study led by study by neurological surgery researchers Nadine Kerr, Ph.D, Helen Bramlett, Ph.D. and Jae Lee, Ph.D., as well as Dr. Dietrich, deploys next-generation, single-cell genomic analyses to determine how various subtypes of neurons, glia and inflammatory cells respond to ischemia, trauma and temperature variations.
For 10 years the Miller School has contributed to the annual “Chilling at the Beach” scientific conferences on therapeutic hypothermia, with experts debating the use of therapeutic hypothermia and targeted temperature management protocols. Miller School faculty and trainees have published more than 100 peer-reviewed articles and collaborate across disciplines, with Drs. Dietrich and Bramlett joining Sylvia Daunert, Pharm.D., Ph.D., and Sapna Deo, Ph.D., from the Department of Biochemistry and Molecular Biology to develop the first intranasal nanodrug that can rapidly induce mild hypothermia.
International hypothermia symposia have also been hosted in Tokyo, Sweden, The Netherlands, Philadelphia and Miami to advance new technologies to cool patients in a controlled and safe manner. In 2011, sustained interest led to the creation of a new journal, Therapeutic Hypothermia and Temperature Management, while 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 a diverse array of countries to work on related projects.
Therapeutic hypothermia remains highly relevant and stands as a success story for the translation of a preclinical therapy to the clinic.
“As research questions continue to evolve and technologies become more sophisticated, I 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.
Tags: brain injury, Department of Neurological Surgery, Department of Neurology, Dr. W. Dalton Dietrich III, hypothermia, spinal cord injury, The Miami Project to Cure Paralysis