Determinants of Outcomes After Head Cooling for Neonatal Encephalopathy

Imperial College London, Londinium, England, United Kingdom
PEDIATRICS (Impact Factor: 5.47). 06/2007; 119(5):912-21. DOI: 10.1542/peds.2006-2839
Source: PubMed

ABSTRACT The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy.
A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 +/- 0.5 degrees C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial).
Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as > or =25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (> or =38 degrees C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy.
Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

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Available from: Marianne Thoresen, Sep 26, 2015
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    • "A proposed diagram (Figure 8) is provided to show that JNK hyperactivation in the neurovascular unit (neurons, endothelial cells and microglia) after HI may be the potential link between being overweight from a small litter size and worsened HI injury in the neonatal brain. Our findings are consistent with a clinical report that evaluated the factors determining the treatment efficacy of head cooling hypothermia in newborns with HI encephalopathy [66]. The study found that larger infants (birth weights of ≥ 25th percentile) displayed a lower frequency of favorable outcomes in the control group, but a greater improvement with cooling. "
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    ABSTRACT: Apoptosis, neuroinflammation and blood-brain barrier (BBB) damage affect the susceptibility of the developing brain to hypoxic-ischemic (HI) insults. c-Jun N-terminal kinase (JNK) is an important mediator of insulin resistance in obesity. We hypothesized that neonatal overweight aggravates HI brain damage through JNK hyperactivation-mediated upregulation of neuronal apoptosis, neuroinflammation and BBB leakage in rat pups. Overweight (OF) pups were established by reducing the litter size to 6, and control (NF) pups by keeping the litter size at 12 from postnatal (P) day 1 before HI on P7. Immunohistochemistry and immunoblotting were used to determine the TUNEL-(+) cells and BBB damage, cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP), and phospho-JNK and phospho-BimEL levels. Immunofluorescence was performed to determine the cellular distribution of phospho-JNK. Compared with NF pups, OF pups had a significantly heavier body-weight and greater fat deposition on P7. Compared with the NF-HI group, the OF-HI group showed significant increases of TUNEL-(+) cells, cleaved levels of caspase-3 and PARP, and ED1-(+) activated microglia and BBB damage in the cortex 24 hours post-HI. Immunofluorescence of the OF-HI pups showed that activated-caspase 3 expression was found mainly in NeuN-(+) neurons and RECA1-(+) vascular endothelial cells 24 hours post-HI. The OF-HI group also had prolonged escape latency in the Morris water maze test and greater brain-volume loss compared with the NF-HI group when assessed at adulthood. Phospho-JNK and phospho-BimEL levels were higher in OF-HI pups than in NF-HI pups immediately post-HI. JNK activation in OF-HI pups was mainly expressed in neurons, microglia and vascular endothelial cells. Inhibiting JNK activity by AS601245 caused more attenuation of cleaved caspase-3 and PARP, a greater reduction of microglial activation and BBB damage post-HI, and significantly reduced brain damage in OF-HI than in NF-HI pups. Neonatal overweight increased HI-induced neuronal apoptosis, microglial activation and BBB damage, and aggravated HI brain damage in rat pups through JNK hyperactivation.
    Journal of Neuroinflammation 04/2011; 8(1):40. DOI:10.1186/1742-2094-8-40 · 5.41 Impact Factor
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    • "These clinical trials indicated that hypothermia can have moderate beneficial effects when the intervention is started within 6 h after the insult in term infants with mild HI damage. Unfortunately, there is little benefit in infants with severe HI brain damage (Jacobs et al., 2007; Wyatt et al., 2007). In addition, hypothermia has not been used in preterm infants. "
    Brain Behavior and Immunity 08/2010; 24. DOI:10.1016/j.bbi.2010.07.029 · 5.89 Impact Factor
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    • "These animal data are strongly supported by clinical observations. Relatively high body temperatures of infants during usual care after hypoxia–ischemia are associated with increased risk of adverse outcomes [16] [36]. "
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    ABSTRACT: Neonatal anoxia is an example of early-life threatening experience that might exert long-lasting behavioral disturbance. One of the consequences of neonatal asphyxia is hyperactivity in open-field test. Changes in open-field activity are coupled with changes in the function of the hypothalamic-pituitary-adrenal (HPA) axis. A critical determinant of the severity of hypoxic-ischemic brain injury in newborn rats is body temperature. Hyperthermia under anoxic conditions increases locomotor activity in the open-field test. Therefore, the aim of the present study was to test whether body temperature during neonatal anoxia can affect basal and stress-induced corticosterone secretion in rats. At the age of 2 days Wistar rat pups were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 degrees C (typical for the rat pups), or was elevated to a level typical for febrile adults (39 degrees C). Control rats were exposed to atmospheric air under the respective thermal conditions. Basal and stress-induced corticosterone levels were assessed using sulphuric acid-induced fluorescence, on postnatal day 14. Body temperature during neonatal asphyxia altered the early developmental profile of plasma corticosterone. Hyperthermia under anoxic conditions decreased the corticosterone response to open-field stress. In conclusion, febrile body temperature changes corticosterone release, which might induce neurobehavioral disturbances. On the other hand, a protection against the HPA dysfunction can be achieved by the reduced physiological neonatal body temperature.
    Neuroscience Letters 03/2010; 472(1):68-72. DOI:10.1016/j.neulet.2010.01.060 · 2.03 Impact Factor
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