Measurement of Intracranial Pressure in Freely Moving Rats.

Brain injury, such as from stroke and trauma, can be complicated by elevated intracranial pressure (ICP). Although raised ICP can be a significant determinant of morbidity and mortality, clinical studies often report widely varying ICP measurements depending on location of measurement and technique used. For the same reasons, reported ICP measurements also vary widely in animal models. The need for anesthesia or tethered connections with some methods of ICP measurement in animals may introduce additional confounds. Moreover, these methods are not well suited for prolonged, continuous measurement. Here, we describe an approach to continually measure ICP in awake, freely moving rats for several days. This technique uses a commercially available, wireless pressure sensor mounted on the head to measure ICP from the epidural space via a fluid-filled catheter. We have demonstrated that this approach reliably detects elevations in ICP that last for several days after ischemic and hemorrhagic strokes in rat.

Delayed localized hypothermia reduces intracranial pressure following collagenase-induced intracerebral hemorrhage in rat.

Brain injury, such as from intracerebral hemorrhage (ICH), causes edema and raises intracranial pressure (ICP)--a potentially life-threatening complication. Clinical studies suggest that therapeutic hypothermia (TH) reduces edema and ICP after ICH. Similarly, animal studies show that TH can sometimes reduce edema, but whether ICP would be attenuated is not known. Here we tested whether 24-h delayed TH reduces edema and ICP in rats with severe striatal ICH (collagenase model). First, we showed that ICH increased epidural ICP (mean of 18 vs. 6.5mm Hg in controls), measured via telemetry. Second, we confirmed that delayed TH did not affect hematoma size at 7d ay (~65 vs. ~61 µL in controls). A cranial cooling device lowered striatal temperature to ~33 °C from 24 to 72 h after ICH. Third, we compared normothermic rats to those with TH that were rewarmed immediately or over 6h. Both TH protocols significantly reduced average and peak ICP by the second treatment day, and benefits persisted after rewarming. However, TH with slow rewarming failed to mitigate edema at 96 h (83.2% vs. 83.6% in controls) whereas rapid rewarming worsened edema (85.7%). Finally, we compared normothermic and TH rats without rewarming and found no impact on edema at 72 h (~81%). In summary, it appears that 24-h delayed local TH lowers ICP by a mechanism other than edema. Rapid rewarming worsens edema after local cooling, but this did not markedly impact ICP. Thus, TH should reduce ICP in patients with severe ICH, but not necessarily through mitigating edema.

Localized hypothermia aggravates bleeding in the collagenase model of intracerebral hemorrhage.

Animal studies testing whether therapeutic hypothermia is neuroprotective after intracerebral hemorrhage (ICH) have been inconclusive. In rodents, ICH is often produced in the striatum by infusing collagenase, which causes prolonged hemorrhaging from multiple vessels. Our previous data shows that this bleeding (hematoma) is worsened by systemic hypothermia given soon after collagenase infusion. In this study we hypothesized that localized brain hypothermia would also aggravate bleeding in this model (0.2 U of collagenase in 1.2 µL of saline). We also evaluated cooling after intrastriatal thrombin infusion (1 U in 30 µL of saline)-a simplified model of ICH thought to cause bleeding. Focal hypothermia was achieved by flushing cold water through an implanted cooling device attached to the skull underneath the temporalis muscle of adult rats. Previous work and data at this time shows this method cools the striatum to ∼33°C, whereas the body remains normothermic. In comparison to normothermic groups, cooling significantly worsened bleeding when instituted at 6 hours (∼94 vs. 42 µL, p=0.018) and 12 hours (79 vs. 61 µL, p=0.042) post-ICH (24-hour survival), but not after a 24-hour delay (36-hour survival). Rats were cooled until euthanasia when hematoma size was determined by a hemoglobin-based spectrophotometry assay. Cooling did not influence cerebral blood volume after just saline or thrombin infusion. The latter is explained by the fact that thrombin did not cause bleeding beyond that caused by saline infusion. In summary, local hypothermia significantly aggravates bleeding many hours after collagenase infusion suggesting that bleeding may have confounded earlier studies with hypothermia. Furthermore, these findings serve as a cautionary note on using cooling even many hours after cerebral bleeding.