SAN DIEGO —Keeping a “cool head” may well optimize neurologic outcomes for patients with ischemic or traumatic brain injury or severe blood loss, according to Patrick M. Kochanek, MD, Director of Safar Center for Resuscitation Research at the University of Pittsburgh. At the Society for Critical Care Medicine’s annual meeting, Dr. Kochanek discussed experiments illustrating hypothermia’s role in minimizing brain damage, and he described biochemical approaches being used to explore the mechanisms behind the technique’s success.[1]

HYPOTHERMIA IMPROVES OUTCOMES

“Certainly, in the lab, hypothermia is the most powerful therapy currently available,” Dr. Kochanek remarked. In early clinical trials of brain trauma patients, hypothermia decreased the need for intracranial pressure reduction and limited the extent of neurologic deficits at three and six months post-injury.[2] Results of more recent studies have been negative, however.[3] This inconsistency is probably because of delays in cooling and other flaws in study methodology, Dr. Kochanek suggested. Although optimal application of hypothermia in brain trauma patients remains unclear, mild cooling (34°C) after cardiac arrest shows promise for reducing neurologic dysfunction.[4,5] Furthermore, mild hypothermia is a simple, safe, and inexpensive therapy.

To illustrate the potential for hypothermia, Dr. Kochanek described the “suspended animation” approach developed by his colleagues Peter J. Safar, MD, and Samuel Tisherman, MD, for minimizing neurologic damage after massive trauma-induced blood loss.[6,7] In dog models of exsanguination cardiac arrest, they tested an aortic flush strategy, which he described as a “balloon catheter in the aortic arch, flushed with different solutions … at different temperatures” to reduce brain temperature. Cardiac arrest was induced with electric shock after five minutes of rapid exsanguination; arrest duration was varied from 20 minutes to two hours. Two minutes after initiating arrest, the researchers began an aortic flush with either room-temperature or iced (2°C to 4°C) saline solutions to achieve tympanically measured brain temperatures ranging between 10°C and 36°C. Dogs were then resuscitated with cardiopulmonary bypass and received intensive care for 72 hours.

A 500-mL/kg flush of saline at either room temperature or 4°C following a 20-minute arrest produced brain temperatures of 36°C or 34°C, respectively. This temperature drop is “not profound cooling by any stretch of the imagination,” Dr. Kochanek stressed. But, even this mild cooling normalized outcomes after an arrest of 20 minutes.

Could the addition of a drug improve on mild hypothermia? The researchers looked at 14 different pharmacologic strategies, said Dr. Kochanek. “The only drug that seemed to augment the protocol was tempol, a brain-penetrating antioxidant” that mimics superoxide dismutase.[8]

The group also explored using larger-volume (up to 500 mL/kg) cold (2°C to 4°C) flushes to achieve various target brain temperatures during a 60-, 90-, or 120-minute arrest. With brain temperatures of 10°C, excellent outcomes after 60- or 90-minute arrest were achieved using this strategy, said Dr. Kochanek. With arrests longer than 30 minutes, damage to other organ systems and the spinal cord distal to the flush did still occur. This damage was mitigated, however, when the researchers proceeded to “first flush the brain, reach target temperature, then pull the catheter back and continue flushing,” Dr. Kochanek pointed out.

The experimenters also evaluated the role of delay between cardiac arrest and initiation of flush: Initiating a 100-mL/kg flush within five minutes after the start of a 30-minute arrest yielded good protection, but outcomes worsened with an eight-minute delay. Thus, timing might crucially limit this procedure’s clinical application.

Dr. Kochanek concluded that four variables are important for outcome: flush temperature, flush volume, time between arrest and flush, and, at longer arrest times, balloon catheter position. “These factors all determine the onset, depth, and distribution of hypothermia,” he emphasized, adding, “the only drug that made a difference was one antioxidant.”[8] The success of these animal studies suggests, said Dr. Kochanek, that “ice-cold, large-volume aortic flush is really ready for clinical trials.” However, he noted, these trials should be performed first on patients “in the setting of compassionate use on otherwise hopeless cases,” such as those with refractory traumatic arrests.

COOLING LIMITS NEURON DEATH

Although controlling edema is essential for managing brain trauma, “we do a pretty good job of this” already, argued Dr. Kochanek; therefore, breakthroughs are more likely to come in the prevention of neuronal death. Dr. Kochanek listed energy failure, excitotoxicity, oxidative stress, and traumatic disconnection of neuron–neuron contacts as potential factors contributing to cell death.

Dr. Kochanek showed results in mice demonstrating that many neurons within impact-induced focal cortical contusions suffer extensive DNA damage and die in a delayed fashion. However, cooling the mice to 32°C for one hour immediately after impact and gradually rewarming them to 37°C during the next hour yielded “dramatic preservation of these neurons at 24 hours after the injury,” he said.

MECHANISMS AFFECTED BY HYPOTHERMIA: A BIOCHEMICAL APPROACH

Despite the attention currently being given to gene array chips and other genetic methods for analyzing the cellular responses to treatment, a genomic approach may not be the best for studying responses of brain tissue to traumatic injury or hypothermia, Dr. Kochanek told the audience: “It tells what’s induced or what isn’t induced ... [but] the correlation between messenger RNA and protein is only about 50%,” even in normal tissue. He added, “In the setting of trauma and ischemia, this association is likely to be even poorer.”

In contrast, two-dimensional gels that separate proteins by mass and by isoelectric pH enable researchers to assess subtle trauma- or treatment-induced changes in all proteins within cells—including functionally important modifications, such as phosphorylation. “It overcomes the key limitation of gene chip technology in that it’s assessing proteins, rather than messenger RNA,” Dr. Kochanek explained.

Work by Larry Jenkins, PhD, at the Safar Center has demonstrated reductions in cytoskeletal proteins, as well as increases in putative neuroprotectants, such as copper-zinc superoxide dismutase, in young rats following trauma. Cell-signaling proteins were also affected. The technique can also reveal multiple phosphorylations of a given protein. “After injury, there’s a loss of phosphorylation in this area of the gel, consistent with loss of a neuroprotective cascade,” Dr. Kochanek noted. Thus, two-dimensional gels could “aid in unraveling some of the mechanisms of secondary damage,” revealing degradation, timing, and interaction of pathways in cell damage, he speculated.

—Mimi Zucker, PhD

References
1. Kochanek P. From the ABCs to proteomics: hunting for the next breakthrough in brain resuscitation (Asmund S. Laerdal memorial lecture). Presented at: Society for Critical Care Medicine’s 31st International Educational and Scientific Symposium; Jan 27, 2002; San Diego, Calif.
2. Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336:540-546.
3. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556-563.
4. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.
5. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.
6. Safar P, Tisherman SA, Behringer W, et al. Suspended animation for delayed resuscitation from prolonged cardiac arrest that is unresuscitable by standard cardiopulmonary-cerebral resuscitation. Crit Care Med. 2000;28(suppl):N214-N218.
7. Safar P, Tisherman SA. Suspended animation for delayed resuscitation. Curr Opin Anaesthesiol. 2002;15:203-210.
8. Behringer W, Safar P, Kentner R, et al. Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs. J Cereb Blood Flow Metab. 2002;22:105-117.

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