Student Corner: Investigating the Uses of TTM

Student Corner is a bimonthly column discussing research projects and interest areas among current EMT and paramedic students. To be featured in this column, contact editor@emsworld.com. 

Targeted temperature management (TTM) is the intentional lowering of body or brain temperature with the objective of reducing tissue damage in the central nervous system and making time to resolve the original pathological issues a patient has encountered.¹

Inducing moderate hypothermia (from the average body temperature of around 37°C to around 32°C) has become a leading neuroprotective intervention in clinical therapy.¹ Formerly known as therapeutic hypothermia (TH), this treatment plan can be administered either systematically or selectively.

The systematic application of TTM employs external solutions such as cold compresses and cooling blankets alongside invasive solutions such as intravascular catheters to cool the entire body. The selective application cools a particular area of the body such as the brain or torso; this cooling process occurs more rapidly and with less fluid than is required for systematic cooling.

In addition, selective TTM minimizes potential side effects of systemic TTM since fluids are directed to a localized region.² This intentional and regulated hypothermia has numerous tissue-specific benefits, such as decreasing excitotoxicity, limiting inflammation, preventing ATP depletion, reducing free radical production, and curbing intracellular calcium overload to avoid apoptosis.

Neurological Applications

Currently TTM has become a standard in postresuscitative care and treatment for perinatal asphyxia. However, evidence indicates hypothermia could be useful for treating additional neurologic injuries, such as stroke, subarachnoid hemorrhage (SAH), and traumatic brain injury (TBI).²

Cardiac arrest and neonatal encephalitis—TTM has long been identified as a potential treatment option for return of spontaneous circulation (ROSC) patients post-cardiac arrest and neonates suffering from encephalitis (inflammation of the brain). Induction of moderate hypothermia before cardiac arrest has been used successfully since the 1950s to protect the brain against global ischemia that occurs during some open-heart surgeries.³ 

After years of preclinical and clinical trials, the American Heart Association released an advisory statement in 2003 about the use of TH in emergency medicine after cardiac arrest that recommended patients who experience ROSC to be cooled to 32°C–34°C for 12–24 hours when their initial rhythm was ventricular fibrillation.³ Subsequent guidelines, however, have recommended against prehospital cooling post-cardiac arrest.

Considering pediatric patients experiencing encephalitis, which represents a model of global brain ischemia much like cardiac arrest, TTM is one of the most intuitive and direct ways for healthcare providers to combat brain swelling. From the conglomerated publications of clinical encephalitis researchers, there is substantial evidence that this treatment reduces the risk of death or disability in infants.¹ 

Acute ischemic stroke and transient ischemic attack—Stroke is the second-leading cause of death and third-leading cause of disability globally. Despite this, current treatment options for acute ischemic stroke (AIS) are severely limited by time and resources, have proven to be costly to both patient and provider, and are available only to those with access to modern and state-of-the-art healthcare. 

While TTM has been widely used for neuroprotection for global ischemia post-cardiac arrest, recent evidence suggests hypothermia may be the neuroprotective agent stroke patients desperately need.² A recent small animal study of AIS indicated hypothermia may reduce the neuronal release of high-mobility group box 1 (HMGB-1), which is well established as a mediator of inflammation and damage during brain ischemia.

However, this HMGB-1 study also demonstrated the time-sensitive nature of productive TTM neuroprotection. TTM is most effective when initiated immediately after or even before ischemia occurs. When TTM initiation is delayed by more than half an hour, it fails to provide adequate neuroprotection in these small animal models.² 

Traumatic brain injury—Traumatic brain injury is the primary cause of worldwide morbimortality in those under age 45.¹ In TBI cases TTM works to delay the effects of hypoperfusion and hemorrhage. Among hemorrhagic strokes, SAH is a particular case that highlights the usefulness of TTM as a treatment option. These patients exhibit a high rate of hyperthermia post-injury, as much as 70% during the first 10 days, which is impeded by cooling therapy.

A research review in 2012 collected 13 randomized clinical trials and 5 observational studies concerning intracranial hypertension management in patients with TBI using therapeutic hypothermia. A significant reduction in intracranial pressure was evident in all patients.² In the field applying external solutions like cold compresses to the patient’s head is a simple example of staving off further injury in the same way so the patient has a wider window to treat trauma.

Future Directions

The wealth of clinical research on TTM has catalyzed improvements in treatment options for ROSC patients both in and out of the hospital, and these developments have made TTM a possible fit for treatment of additional ailments in the prehospital setting. Currently treatment with hypothermia is standard medical care after VT/VF cardiac arrest-related coma and neonatal encephalopathy, yet TTM has been shown to improve outcomes for AIS, SAH, and TBI as well.² 

Many of the animal and mathematical models discussed in this column have yet to be applied to EMS practice, of course. More research is required to elucidate the impact of rapid-response TTM in the field because many details remain undiscovered, such as the exact time window for each pathology, rewarming protocols, adequate therapeutic markers, and what therapies would offer better neuroprotection in combination with hypothermia. In all, successful TTM in the prehospital setting is a possible treatment for more injuries than previously employed, but there is more that must be understood for the treatment to become conventional practice.  

References

1. Andresen M, Gazmuri JT, Marín A, Regueira T, Rovegno M.
Therapeutic hypothermia for acute brain injuries. Scand J Trauma Resusc Emerg Med, 2015 Jun 5; 23: 42. 

2. Huber C, Huber M, Ding Y. Evidence and opportunities of hypothermia in acute ischemic stroke: Clinical trials of systemic versus selective hypothermia. Brain Circ, 2019 Dec 27; 5(4): 195–202. 

3. Nolan JP, Morley PT, Vanden Hoek TL, et al.; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation, 2003 Jul 8; 108(1): 118–21.

Jacob S. Hershenhouse is a sophomore studying neuroscience at UCLA. He plans to pursue a career in clinical medicine and hopes to further his interests in paramedicine and critical care after graduation.