Delayed whole-body cooling to 33 or 35 degrees C and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet.

OBJECTIVES: Fundamental questions remain about the precise temperature providing optimal neuroprotection after perinatal hypoxia-ischemia (HI). Furthermore, if hypothermia delays the onset of the neurotoxic cascade and the secondary impairment in cerebral energy generation, the "latent phase" may be prolonged, thus extending the period when additional treatments may be effective. The aims of this study were to investigate the effects of delayed systemic cooling at either 33 degrees C or 35 degrees C on the following: (1) latent-phase duration, and (2) cerebral metabolism during secondary energy failure itself, in the 48-hour period after transient HI. METHODS: Piglets were randomly assigned to the following: (1) HI-normothermic (HI-n) rectal temperature (Trectal; n = 12), (2) HI-Trectal 35 degrees C (HI-35; n = 7), and (3) HI-Trectal 33 degrees C (HI-33; n = 10). Groups were cooled to the target Trectal between 2 and 26 hours after HI. Serial magnetic resonance spectroscopy was performed over 48 hours. The effect of cooling on secondary energy failure severity (indexed by the nucleotide triphosphate/exchangeable phosphate pool [NTP/EPP] and phosphocreatine/inorganic phosphate [PCr/Pi] ratios) was assessed. RESULTS: Compared with HI-n, HI-35 and HI-33 had a longer NTP/EPP latent phase and during the entire study duration had higher mean NTP/EPP and PCr/Pi. The latent phase (both PCr/Pi and NTP/EPP) and the whole-brain cerebral energetics were similar for HI-35 and HI-33. During the hypothermic period, compared with HI-n, PCr/Pi was preserved in the cooled groups, but this advantage was not maintained after rewarming. Compared with HI-n, HI-35 and HI-33 had higher NTP/EPP after rewarming. CONCLUSIONS: Whole-body hypothermia for 24 hours at either 35 or 33 degrees C, commenced 2 hours after resuscitation, prolonged the NTP/EPP latent phase and reduced the overall secondary falls in mean PCr/Pi and NTP/EPP during 48 hours after HI. Reducing the temperature from 35 to 33 degrees C neither increased mean PCr/Pi and NTP/EPP nor further lengthened the latent phase.

Neurodevelopmental outcome of preterm infants with ventricular dilatation with and without associated haemorrhage.

This study investigated whether in preterm children who had ventricular dilatation (VD) on neonatal cranial ultrasound outcome at age 8 years was influenced by the additional presence of germinal matrix haemorrhage--intraventricular haemorrhage (GMH-IVH). Six-hundred and ninety-nine preterm infants (<33 wks' gestation, mean 29.6 wks [SD 2.1]) with either normal cranial ultrasound (n=616; 286 females, 330 males), or with VD with (n=66; 32 females, 34 males) or without (n=17; 4 females, 13 males) GMH-IVH were enrolled in the study. At age 8 years outcome was assessed in 567 (81%) of the 699 children by neurological examination, the Test of Motor Impairment (TOMI), the test of Visuo-Motor Integration (VMI), and the Wechsler Intelligence Scales for Children. Results showed that the proportion of children with disabling impairments was higher in the group with VD and GMH-IVH. Performance on TOMI and VMI (even in those without disabling impairments) was poorer in those with VD and GMH-IVH than in children with normal scans or those with VD only. Children with VD and GMH-IVH had significantly lower performance IQ than children with normal ultrasound, whereas those with VD only were not different from those with normal scans. Results suggest the presence of subtle white matter injury that has not been identified by neonatal cranial ultrasound. Although this study did not investigate biochemical markers of haemorrhage, we hypothesize that non-protein-bound iron is likely to be a contributing factor to white matter damage in preterm infants.

Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia.

Hypothermia after perinatal hypoxia-ischemia (HI) is neuroprotective; the precise brain temperature that provides optimal protection is unknown. To assess the pattern of brain injury with 3 different rectal temperatures, we randomized 42 newborn piglets: (Group i) sham-normothermia (38.5-39 degrees C); (Group ii) sham-33 degrees C; (Group iii) HI-normothermia; (Group iv) HI-35 degrees C; and (Group v) HI-33 degrees C. Groups iii through v were subjected to transient HI insult. Groups ii, iv, and v were cooled to their target rectal temperatures between 2 and 26 hours after resuscitation. Experiments were terminated at 48 hours. Compared with normothermia, hypothermia at 35 degrees C led to 25 and 39% increases in neuronal viability in cortical gray matter (GM) and deep GM, respectively (both p < 0.05); hypothermia at 33 degrees C resulted in a 55% increase in neuronal viability in cortical GM (p < 0.01) but no significant increase in neuronal viability in deep GM. Comparing hypothermia at 35 and 33 degrees C, 35 degrees C resulted in more viable neurons in deep GM, whereas 33 degrees C resulted in more viable neurons in cortical GM (both p < 0.05). These results suggest that optimal neuroprotection by delayed hypothermia may occur at different temperatures in the cortical and deep GM. To obtain maximum benefit, you may need to design patient-specific hypothermia protocols by combining systemic and selective cooling.