Protective Effects of Moderate Hypothermia after Neonatal Hypoxia-Ischemia: Short- and Long-Term Outcome

Bona, Elsa; Hagberg, Henrik; Løberg, Else Marit; Bågenholm, Ralph; Thoresen, Marianne

doi:10.1203/00006450-199806000-00005

Cited by 315 publications

(258 citation statements)

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“…The improvement of long-term motor behavior after hypothermia was also demonstrated in a rat model of neonatal HI (4). To date, gender effects of hypothermia were reported only by Bona et al (15), who observed more effective neuroprotection in female rats than in male rats. In the present study, we observed strong neuroprotective effects of hypothermia in female rats but saw weaker effects in male rats.…”

Section: Discussionmentioning

confidence: 85%

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Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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Background: Both hypothermia and erythropoietin (ePO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (hI). We investigated a possible additive effect of the use of a combination of hypothermia-ePO in a rat model of neonatal hI. Methods: at postnatal day 7, rats were subjected to hI and then randomized to 3 h of hypothermia, ePO, or both. sensorimotor function was assessed by the cylinder-rearing test (cRT) at 2 and 5 wk after hI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. results: Multivariable analysis using general linear modeling showed that hypothermia, ePO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after hI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the cRT. Maximal improvement in males was 26% after combined treatment with hypothermia and ePO. histological outcome was improved by hypothermia only with no additional effect of ePO or gender. conclusion: hypothermia after hI improved sensorimotor function in females more than in males. There was a borderline additive effect of ePO when combined with hypothermia. histology of brain lesion volume and white matter damage was improved only by hypothermia.P erinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury and is associated with long-term neurological sequelae such as cognitive dysfunction, developmental delay, seizures, and sensory and/or motor impairment (1,2). Several studies in newborn rodents indicate that reduction of brain temperature by 2-5 °C even for 3 h, when started within 6 h after HI, provides neuroprotection and improved behavioral outcome (3-6).The neuroprotective effects of hypothermia of mildly asphyxiated newborns have been demonstrated, but in clinical practice, morbidity and mortality remain considerable (30-45%) (7,8). The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10-13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO,.The aim of the present study was to test whether the addition of EPO to hypothermia has additive neuroprotective effects as compared with a single treatment and to examine possible gender effects. Results HypothermiaSham-treated rats did not show a paw preference in the cylinder-rearing test (CRT) (paw preference < ±5%, data not shown). A significant paw preference of the unimpaired forepaw in the normothermia groups was observed at both 2 and 5 wk after HI (Figure 1). Differences between males and females in the normothermia group were not statistically significant. In fema...

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Section: Discussionmentioning

confidence: 85%

“…In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO, and 2-iminobiotin (15)(16)(17).…”

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Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

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“…This leads to the question of how to transfer 'time' in a rat model to larger animal models and to humans. With our neonatal HT research that led to effective clinical trial outcome, we found in the rat that 51C to 61C cooling for 3 h (Thoresen et al, 1996b) or 5 h (Bona et al, 1998) was protective, in the pig 24 h of HT (combined selective head cooling and body cooling by 4.51C) was neuroprotective, in the sheep 76 h cooling was effective even after a delayed start of 5.5 h (Gunn et al, 1998), and in humans 72 h of 3.51C cooling was neuroprotective (Gluckman et al, 2005;Shankaran et al, 2005) in clinical trials where cooling on average started 4.5 h after birth.…”

Section: Discussionmentioning

confidence: 99%

Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

Thoresen

Hobbs

Wood

et al. 2009

J Cereb Blood Flow Metab

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Hypothermia (HT) improves outcome after neonatal hypoxia-ischemia. Combination therapy may extend neuroprotection. The noble anesthetic gas xenon (Xe) has an excellent safety profile. We have shown earlier that 3 h of 50% Xe plus HT (321C) additively gives more protection (72%) than either alone (HT = 31.1%, Xe = 10.2%). Factors limiting clinical use include high-cost and specialist administration requirements. Thus, combinations of 1 h of 50% Xe were administered concurrently for either the first (1 h Immediate Xe) or last (1 h Delayed Xe) of 3 h of posthypoxic-ischemic HT as compared with 3 h of 50%Xe/HT to investigate how brief Xe exposure with a delay would affect efficacy. An established neonatal rat hypoxia-ischemia model was used. Serial functional neurologic testing into adulthood was performed, followed by neuropathological examination. Xenon with HT was more effective with longer Xe duration (3 h versus 1 h) (P = 0.015). However, 1 h Xe/3 h HT resulted in better neuroprotection than 3 h HT alone (P = 0.03), this significant effect was also present with 1 h Xe after a 2-h delay. One (immediate or with a delay) or 3 h Xe also significantly improved motor function (P = 0.024). Females had significantly better motor scores than males, but no sex-dependent difference in pathology results. The neuroprotection of short, delayed Xe treatment would allow transport to specialist facilities to receive Xe.

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“…Hypothermic protection was further confirmed in newborn pigs (2-3,36) and fetal sheep (4,37) before successful clinical trials of therapeutic HT (5-7). For the postnatal day 7 rat model to show long-term neuroprotection, at least 3 h of 5 °C reduction in core temperature is needed (31)(32)(33)38). We reduced experimental variability by brief duration of anesthesia (median 5.5 min; two experienced researchers performing ligations in parallel), short duration (<180 min) between carotid ligation and the beginning of hypoxia, and tightly controlled temperature, oxygen, and CO 2 levels in our specially designed exposure chamber (32).…”

Section: Methodsmentioning

confidence: 99%

Resuscitation with 100% oxygen increases injury and counteracts the neuroprotective effect of therapeutic hypothermia in the neonatal rat

et al. 2012

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IntroductIon: Mild therapeutic hypothermia (hT) reduces brain injury in survivors after perinatal asphyxia. Recent guidelines suggest that resuscitation of term infants should be started with air, but supplemental oxygen is still in use. It is not known whether supplemental oxygen during resuscitation affects the protection offered by subsequent hT. results: Wilcoxon median (95% confidence interval) hippocampal injury scores (range 0.0-4.0; 0 to ≥90% injury) were 21% O 2 normothermia (NT): 2.00 (1.25-2.50), 21% O 2 hT: 1.00 (0.50-1.50), 100% O 2 NT: 2.50 (1.50-3.25), and 100% O 2 hT: 2.00 (1.25-2.50). although hT significantly reduced hippocampal injury (B = -0.721, seM = 0.297, P = 0.018), reoxygenation with 100% O 2 increased injury (B = +0.647, seM = 0.297, P = 0.033). Regression constant B = 1.896, seM = 0.257 and normally distributed residuals. dIscussIon: We confirm an ~50% neuroprotective effect of therapeutic hT in the neonatal rat. Reoxygenation with 100% O 2 increased injury and worsened reflex performance. hT was neuroprotective whether applied after reoxygenation with air or 100% O 2 . however, hT after 100% O 2 gave no net neuroprotection. Methods: In an established neonatal rat model, hypoxiaischemia (hI) was followed by 30-min reoxygenation in either 21% O 2 or 100% O 2 before 5 h of NT (37 °c) or hT (32 °c). The effects of hT and 100% O 2 on histopathologic injury in the hippocampus, basal ganglia, and cortex, and on postural reflex performance 7 d after the insult, were estimated by linear regression.P erinatal asphyxia occurs in 1 to 6 per 1,000 term human births (1) and is an important cause of severe neurologic impairment and neonatal mortality. Therapeutic hypothermia (HT) has emerged as a neuroprotective therapy in both newborn animal models (2-4) and clinical trials (5-7). The collective evidence from these studies confirms that mild therapeutic HT improves outcome in hypoxic-ischemic encephalopathy, a condition in which ~50% of cooled infants normally die or have significant neurologic disability (8) as compared with before the advent of HT treatment when ~65% had poor outcome. In the UK, the National Institute for Health and Clinical Excellence has declared that HT should be used as standard of care after perinatal asphyxia (9). HT after perinatal asphyxia is also recommended by the recent 2010 International Resuscitation Guidelines (International Liaison Committee on Resuscitation) (10). HT suppresses many of the pathways that lead to delayed energy failure and cell death after hypoxia (11,12), including generation of reactive oxygen species (13), excitotoxicity (14), and the inflammatory response (15).Supplemental oxygen was previously recommended for resuscitation of the asphyxiated newborn infant, but after the changes in the 2010 International Liaison Committee on Resuscitation guidelines, it is now recommended that resuscitation of the term infant is best started with air, rather than pure oxygen (10). Evidence from animal studies shows that supplemental oxygen during resuscitation...

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Protective Effects of Moderate Hypothermia after Neonatal Hypoxia-Ischemia: Short- and Long-Term Outcome

Cited by 315 publications

References 31 publications

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

Resuscitation with 100% oxygen increases injury and counteracts the neuroprotective effect of therapeutic hypothermia in the neonatal rat

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