Hypothermia for Traumatic Brain Injury: Current Evidence and Future Directions

Introduction

Therapeutic hypothermia—the intentional lowering of temperature in an attempt to mitigate injurious processes—has undergone several life cycles in medical practice. Interest in hypothermia may have first been introduced into medical practice from reports centuries ago suggesting that injured soldiers may survive when kept away from heat sources. More recently, neurological protection has been observed in people who have suffered prolonged cardiac arrests while under ice-cold water ( ). In the 1960s and 1970s, therapeutic hypothermia had become incorporated into many clinical practices for cardiac arrest, traumatic brain injury (TBI), and other conditions and was essential for the development of safe cardiac bypass procedures ( ). Landmark studies have determined that hypothermia improves neurological outcomes in adults after cardiac arrest and in neonates after perinatal asphyxia ( ). However, contemporary research on the utility of therapeutic hypothermia for TBI has been much more mixed. This chapter is intended to summarize the utility of therapeutic hypothermia in TBI by reviewing proposed mechanisms of neurological protection, various management strategies, and the current clinical evidence for its use.

Mechanisms of Protection and Potential Side Effects

Hypothermic neuroprotection has been demonstrated in many preclinical models of injury, with the majority of the studies in TBI being performed in rodents. In these models, hypothermia induced near the time of injury has led to improved behavioral and histologic outcomes ( ). However, the primary mechanisms of hypothermic neuroprotection remain unclear because of the myriad effects hypothermia can have on cell function, organ activity, and metabolic processes. Hypothermia has effects on many secondary injury mechanisms including (1) cerebral metabolism, (2) excitotoxicity, (3) oxidative stress, (4) blood–brain barrier (BBB) permeability, (5) gene expression, (6) neurotrophin levels and function, (7) neuroinflammation, (8) cerebral swelling, and (9) axonal injury. This review will focus on data from TBI models and a few of the most prominent postulated mechanisms: oxidative stress, neuroinflammation, BBB permeability, and neurogenesis.

One of the most compelling examples of bench-to-bedside research of posttraumatic hypothermia has focused on the effects of hypothermia on free radical damage and oxidative stress. Multiple biochemical pathways may lead to free radical production following TBI and the central nervous system may be particularly prone to the deleterious effects of free radicals on neuronal and glial cell survival, vascular function, and neuroinflammation because of the role of lipids in the brain. In children with severe TBI [Glasgow Coma Scale (GCS) score <9], demonstrated a marked and sustained reduction in antioxidant reserve in cerebrospinal fluid over the first several days after injury. This data has been interpreted as evidence for a free radical damage time course and is supported by evidence of lipid peroxidation and protein oxidation. Hypothermia may alter this pathway if it can minimize the damage in a time-dependent manner. In a confirmatory study, found that children with severe TBI who were cooled to 32–33°C for 48 h after severe TBI had preserved total antioxidant reserves and glutathione levels.

The humoral and cellular neuroinflammatory response to TBI has been shown to be temperature dependent. Within the humoral system, two of the primary proinflammatory cytokines responsible for the pathophysiologic response to TBI, tumor necrosis factor-alpha (TNF-α) and IL-1β, are affected by hypothermia. Although hippocampal TNF-α mRNA levels were significantly reduced by posttraumatic hypothermia, TNF-α protein levels were unchanged after 3 h at 33°C. demonstrated that hypothermia decreased expression of the TNF receptor and as well as a shift in TNF signaling from proapoptotic to procell survival pathway. This model has also been used to show hypothermia reduces mRNA and protein levels of IL-1β. It has been postulated that these hypothermia effects may be related to caspase-1 activation, which is the enzyme primarily responsible for processing of pro-IL-1β to the active form and is temperature dependent. The cellular neuroinflammatory response to posttraumatic hypothermia was investigated by using a rat model with a target temperature of 32°C for 4 h; animals treated with hypothermia had a four- to eightfold decrease in acute neutrophil accumulation despite there being no effect on peripheral neutrophil counts.

Compromise of the BBB after trauma can lead to extravasation of bloodborne substances into the brain parenchyma leading to edema, inflammation, and secondary injury and is another target of hypothermia therapies. have shown posttraumatic hypothermia significantly reduced BBB permeability at 3 and 7 days after injury. Matrix-metalloproteinase-9 (MMP-9), a protein that can degrade the basal lamina leading to disruption of the BBB, is significantly increased in the cortex and hippocampus after TBI and is attenuated by therapeutic hypothermia ( ).

examined the effect of posttraumatic hypothermia on neurogenesis. They found that bromodeoxyuridine (BrdU) and doublecortin (DCX) to labeled neuroblasts were increased in the dentate gyrus at 7 days after TBI in hypothermic animals using a fluid percussion model. The methods of this study were insufficient to determine if the effect of hypothermia was based on an increase in actual neurogenesis or simply neuroprotection of existing neuroblasts from TBI-based cell death.

Management Strategies