The Effect of Prolonged Modification of Cerebral Temperature on Outcome after Hypoxic-Ischemic Brain Injury in the Infant Rat

Abstract

Hypoxic-ischemic injuries can evolve over several days, and recent studies suggest that further neuronal death may occur 6 to 72 h later. Because cerebral temperature is an important determinant of outcome during the primary injury, we investigated the effect of temperature, on outcome, during the later phases of injury. Hypoxic-ischemic injury was induced in 21-d-old rats by unilateral ligation of the right carotid artery followed by exposure to 15 min of hypoxia of 8% O2 at 34 degrees C. Cerebral temperature changes were induced by modifying environmental temperature. The rats were divided into four treatment groups: group 1 (n = 15) remained at 34 degrees C for 72 h; group 2 (n = 14) were kept at 34 degrees C for 6 h and then at 22 degrees C for the remaining 66 h; group 3 (n = 17) remained at 22 degrees C for 6 h and 34 degrees C for the next 66 h; group 4 (n = 16) remained at 22 degrees C for 72 h. Rats kept at 22 or 34 degrees C had cortical temperatures of 35.5 +/- 0.1 degrees C and 37.9 +/- 0.2 degrees C, respectively. Histologic outcome was assessed 72 h after hypoxia. The area of cortical infarction was reduced in group 4 compared with groups 1-3 (p < or = 0.05). Striatal damage was reduced in group 4 (p = 0.05). Hippocampal neuronal loss was not significantly altered. In a subsequent study the area of cortical infarction was 12.1 +/- 3 mm2 in group 1 (n = 11) compared with 3.4 +/- 1.5 mm2 group 4 treated rats (n = 10) 21 d after the injury (p < 0.01). Thus hypothermia spanning both the first 6 h and from 6 to 72 h after injury was needed to improve outcome. Conversely exposure to the thermoneutral environment exacerbated the injury. These observations suggest that prolonged moderate cerebral hypothermia can be used to suppress the cytotoxic processes that occur after hypoxic-ischemic injury.

Hypothermic neuroprotection

“…For example, in unanesthetized infant rats subjected to moderate hypoxia-ischemia, mild hypothermia (2 to 3°C decrease in brain temperature) for 72 hours from the end of hypoxia prevented cortical infarction, while 6 hours of cooling had an intermediate effect. 70 In the same model, however, a greater reduction in body temperature, of 5°C, for 6 hours, starting immediately after the insult, gave significant neuroprotection both after 1 and 6 weeks survival as well as neurobehavioral improvement. 75 Similarly, in anesthetized piglets exposed to either hypoxia with bilateral carotid ligation or to hypoxia with hypotension, either 12 hours of mild whole body hypothermia (35 o C) or 24 hours of head cooling with mild systemic hypothermia started immediately after hypoxia prevented delayed energy failure, 76 reduced neuronal loss 55,77 and suppressed post-hypoxic seizures.…”

“…93 The most likely explanation is that the duration and / or degree of hypothermia may have been inadequate as suggested by the finding that cooling by 5°C for 6 hours 75 or 72 hours of very mild cooling in infant rats were associated with long-term improvement after carotid occlusion and hypoxia. 70 Subsequent studies both in the 7 day rat and in adult species have confirmed that a sufficiently prolonged phase of moderate cooling can be associated with persistent behavioral and histological protection for many weeks and months. 75,83,84,87,94 -96 Broadly, these studies tend to suggest that the later cooling is started, the more prolonged the treatment needs to be for neuroprotection.…”

Persistent Neuroprotection with Prolonged Postischemic Hypothermia in Adult Rats Subjected to Transient Middle Cerebral Artery Occlusion

“…Studies in newborn and fetal models of hypoxiaischemia similarly suggest that delayed hypothermia reduces injury (21,22,39). One study (39) in 21-day-old rats illustrates that 72 h of cooling is more efficacious than a 6-h duration and that persistent (3 weeks) cortical neuroprotection occurs with protracted hypothermia.…”

“…One study (39) in 21-day-old rats illustrates that 72 h of cooling is more efficacious than a 6-h duration and that persistent (3 weeks) cortical neuroprotection occurs with protracted hypothermia. As with the adult studies, the optimal pattern of hypothermia has yet to be defined.…”

Therapeutic Hypothermia for Management of Neonatal Asphyxia: What Nurses Need to Know

“…Another treatment, which has been studied widely, initially in animals 23,24 and then in neonates, [25][26][27][28][29][30] is therapeutic hypothermia. The reduction of body temperature by 3ºC to 5ºC less than normal body temperature during reperfusion before secondary energy failure occurs, can reduce cerebral injury.…”