Minimal systemic hypothermia combined with selective head cooling evaluated in a pig model of hypoxia-ischemia

Abstract

Background: Selective head cooling (SHC) with moderate hypothermia (HT) and whole-body cooling are beneficial following perinatal asphyxia. SHC with systemic normothermia (NT) or minimal HT is under-investigated, could obviate systemic complications of moderate HT, and be applicable to preterm infants. We hypothesized that minimal systemic HT with SHC following hypoxia-ischemia (HI) would be neuroprotective compared with systemic NT. Methods: Newborn pigs underwent global HI causing permanent brain injury before being randomized to NT (rectal temperature (T rectal ) 38.5 °C) or minimal HT (T rectal 37.0 °C) with SHC (cooling cap and body wrap) for 48 h followed by 24-h NT with 72-h survival. results: SHC did not reduce global or regional neuropathology score when correcting for insult severity or compared with a NT group matched for HI severity but increased mortality by 26%. During 48 h, the SHC mean ± SD T rectal was 37.0 ± 0.2 °C, and T deep brain and T superficial brain were 35.0 ± 1.1 °C and 31.5 ± 1.6 °C, respectively, with stable T brain achieved ≥3 h after starting cooling. conclusion: This is the first study in newborn pigs of minimal systemic HT with SHC for 48 h and a further 24 h of NT following HI. Mortality was increased in the cooled group with no neuroprotection in survivors. t herapeutic hypothermia (HT) using whole-body cooling (WBC) to a rectal temperature (T rectal ) of 33.5 °C or selective head cooling (SHC) with moderate systemic HT to 34.5 °C is the only effective treatment for hypoxic ischemic encephalopathy (HIE) in term infants (1). HIE also occurs in preterm infants and HT trials are planned (e.g., Preemie Hypothermia for Neonatal Encephalopathy, NCT01793129) but concerns remain about systemic adverse effects (2-4). SHC without moderate systemic HT is under-investigated and is suggested to reduce potential systemic complications of whole body-HT. Reducing deep-brain temperature (T deep brain ) using SHC in term infants is difficult but may be easier in preterm infants with their smaller head size, thinner skin, and skull (5). In newborn pigs, T deep brain is within 1 °C of core temperature at normothermia (NT) but during SHC there is a gradient of between 3 and 7 °C (6-9). SHC may offer an advantage over WBC because different brain regions may have different optimum temperatures for neuroprotection (9-11).Short-term SHC with systemic NT is possible experimentally but neuroprotection has not been assessed using an adequate treatment period using clinically available equipments (12-14). We showed previously that SHC combined with moderate systemic HT to 33.5 °C was neuroprotective using a global model of perinatal hypoxia-ischemia (HI) in the newborn pig (8). We hypothesized that minimal systemic HT (1.5 °C below core temperature) combined with SHC for 48 h would be neuroprotective compared with systemic NT using a validated neuropathology score. RESULTSThere were no differences in age, weight, sex distribution or baseline arterial pH, lactate, and blood glucose between groups ( Table 1)...

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…Although the effectiveness of hypothermia against the development of perinatal encephalopathy has been clinically demonstrated (44,66), application of hypothermia to prevent brain injuries in extremely preterm infants remains to be investigated, since concerns regarding adverse effects remain, and intrainsult hypothermia, as used in the present study, would be invasive to the infants and mothers (67,68). Application of therapeutic hypothermia to the extremely preterm infants may not be entirely practical at present, even if only head-specific cooling were considered (69,70). However, it might be possible to modify brain injuries in human extremely preterm infants if the molecular mechanisms underlying the effectiveness of hypothermia were identified, in order to prevent subsequent neurobehavioral complications in extremely preterm infants.…”