Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Marianne Thoresen
Publications and source records attributed to Marianne Thoresen.
Translational stroke research in the developing brain.
Preclinical animal models can help guide the development of clinical pediatric and newborn stroke trials. Data obtained using currently available models of hypoxia-ischemia and focal stroke have demonstrated the need for age-appropriate models. There are age-related differences in susceptibility of the immature brain to oxidative stress and inflammation, as well as in the rate and degree of apoptotic neuronal death. These issues need to be carefully addressed in designing future clinical trials.
Adult↗
Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia.
BACKGROUND AND PURPOSE: Brain injury after hypoxic-ischemic insults evolves via an apoptotic/necrotic cascade. Glutamate over release and N-methyl-d-aspartate (NMDA) receptor over activation (excitotoxicity) are believed to trigger this process. Xenon is a nontoxic anesthetic gas that reduces neurotransmitter release and functionally antagonizes NMDA receptors. Administering xenon to hypoxic-ischemic newborns might be clinically effective if the neurotoxic processes continue evolving after delivery. We sought to determine whether xenon administration after the initial hypoxic-ischemic insult was neuroprotective. METHODS: Fifty 7-day-old rats received a 90-minute hypoxic insult after unilateral carotid ligation. They were then randomized to breathe 1 of 2 gas mixtures for 3 hours: 50% Xe/30% O2/20% N2 or 30% O2/70% N2. RESULTS: One week after hypoxic-ischemic survival, significant global protection was seen in the xenon group (80% less injury); cortex/white matter (88% versus 25%), hippocampus (62% versus 0%), basal ganglia (81% versus 25%), and thalamus (50% versus 0%; percentage of global damage score in nonxenon versus xenon groups, respectively). CONCLUSIONS: Three hours of xenon administration commenced after hypoxia-ischemia in neonatal rats provides short-term neuroprotection. This finding suggests that treatment with xenon after perinatal asphyxia would also be neuroprotective. Because xenon does not cause other neurotoxic effects and has demonstrated minimal side effects in extensive anesthesia studies, it would make an ideal candidate for the treatment after human perinatal hypoxia-ischemia.
Anesthetics, Inhalation↗
Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant.
PURPOSE OF REVIEW: This review examines recent findings from experimental models and clinical trials of induced hypothermia as treatment after cerebral hypoxia-ischaemia in term newborn infants. RECENT FINDINGS: Experimental hypothermia inhibits many steps in the biochemical cascade that produces severe brain injury after hypoxia-ischaemia. This is in contrast to pharmacological agents, which tend to target only one step in the process that leads to brain injury. In adult humans hypothermia initiated immediately after cardiac arrest has improved outcomes. Delayed cooling after brain trauma has also been effective in a subgroup of adult patients. Seventy-two hours of selective head cooling with mild systemic hypothermia (rectal temperature 34.5 degrees C) in term infants with hypoxic-ischaemic encephalopathy (HIE) reduced death or disability in the infants with less severe electroencephalographic changes at entry (no benefit in those with advanced electroencephalographic changes). Cooling had no apparent adverse effects. A smaller randomized clinical trial of 48 h whole body cooling (rectal T 33 degrees C) found a reduction in death and neurological impairment. SUMMARY: In term infants with HIE there is emerging evidence that both selective head cooling and whole body cooling are neuroprotective and safe. This is consistent with a wealth of experimental animal data and adult trials. Neuroprotection seems to be lost if cooling is started after 6 h. The challenge now is to complete ongoing trials. If meta-analysis confirms a therapeutic effect, then this may lead to selection criteria and treatment protocols for very early hypothermia in HIE at term.
Asphyxia Neonatorum↗
Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy.
Hypothermia induced by whole-body cooling (WBC) and selective head cooling (SHC) both reduce brain injury after hypoxia-ischemia in newborn animals, but it is not known how these treatments affect the incidence or pattern of brain injury in human newborns. To assess this, 14 term infants with hypoxic-ischemic encephalopathy (HIE) treated with SHC, 20 infants with HIE treated with WBC, and 52 noncooled infants with HIE of similar severity were studied with magnetic resonance imaging in the neonatal period. Infants fulfilling strict criteria for HIE were recruited into the study after assessment of an amplitude-integrated electroencephalography (aEEG). Cooling was commenced within 6 hours of birth and continued for 48 to 72 hours. Hypothermia was not associated with unexpected or unusual lesions, and the prevalence of intracranial hemorrhage was similar in all 3 groups. Both modes of hypothermia were associated with a decrease in basal ganglia and thalamic lesions, which are predictive of abnormal outcome. This decrease was significant in infants with a moderate aEEG finding but not in those with a severe aEEG finding. A decrease in the incidence of severe cortical lesions was seen in the infants treated with SHC.
Brain↗
The pathogenesis of neonatal post-hemorrhagic hydrocephalus.
Hydrocephalus after intraventricular hemorrhage (IVH) has emerged as a major complication of preterm birth and is especially problematic to treat. The hydrocephalus is usually ascribed to fibrosing arachnoiditis, meningeal fibrosis and subependymal gliosis, which impair flow and resorption of cerebrospinal fluid (CSF). Recent experimental studies have suggested that acute parenchymal compression and ischemic damage, and increased parenchymal and perivascular deposition of extracellular matrix proteins--probably due at least partly to upregulation of transforming growth factor-beta (TGF-beta)--are further important contributors to the development of the hydrocephalus. IVH is associated with damage to periventricular white matter and the damage is exacerbated by the development of hydrocephalus; combinations of pressure, distortion, ischaemia, inflammation, and free radical-mediated injury are probably responsible. The damage to white matter accounts for the high frequency of cerebral palsy in this group of infants. The identification of mechanisms and mediators of hydrocephalus and white matter damage is leading to the development of new treatments to prevent permanent hydrocephalus and its neurological complications, and to avoid shunt dependence.
Animals↗
Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective.
Hypothermia is potentially therapeutic in the management of neonatal hypoxic-ischemic brain injury. However, not all studies have shown a neuroprotective effect. It is suggested that the stress of unsedated hypothermia may interfere with neuroprotection. We propose that selective head cooling (SHC) combined with mild total-body hypothermia during anesthesia enhances local neuroprotection while minimizing the occurrence of systemic side effects and stress associated with unsedated whole-body cooling. Our objective was to determine whether SHC combined with mild total-body hypothermia while anesthetized for a period of 24 hours reduces cerebral damage in our piglet survival model of global hypoxia-ischemia. Eighteen anesthetized piglets received a 45-minute global hypoxic-ischemic insult. The pigs were randomized either to remain normothermic or to receive SHC. We found that the severity of the hypoxic-ischemic insult was similar in the SHC versus the normothermic group, and that the mean neurology scores at 30 and 48 hours and neuropathology scores were significantly better in the SHC group versus the normothermic group. We conclude that selective head cooling combined with mild systemic hypothermia and anesthesia is neuroprotective when started immediately after the insult in our piglet model of hypoxic-ischemic encephalopathy.
Anesthesia↗
Posthemorrhagic ventricular dilation in the neonate: development and characterization of a rat model.
Intraventricular hemorrhage is a common complication of prematurity. Posthemorrhagic ventricular dilation (PHVD) has a high rate of disability and no safe and effective treatment. Its pathogenesis is poorly understood, largely because of the lack of a satisfactory animal model. We have developed a model of neonatal PHVD in the rat. Seven-day-old (P7) Wistar rat pups were given 80-microl injections of citrated rat blood or artificial cerebrospinal fluid (CSF) into alternate lateral ventricles on P7 and P8. Intracranial pressure was monitored and increased briefly by over 8-fold. Some rats received further 10-microl intraventricular injections of India ink on P21. Animals were weighed daily and simple neurologic tests performed. On P21 (or P22 if India ink had been injected), the rats were perfusion-fixed and blocks processed for paraffin histology. Sixty-five percent of pups injected with blood and 50% injected with artificial CSF developed dilated lateral ventricles, with patchy loss of ependyma, marked astrocytic gliosis, and rarefaction of periventricular white matter. India ink injection revealed slow transit of CSF from the dilated lateral ventricles but eventual passage into the subarachnoid space. Pups that had received intraventricular injections but did not develop ventricular dilation nonetheless had lighter brains than littermate controls (p < 0.001). Body weights were not significantly different from controls. Hydrocephalic animals had reduced motor performance as assessed by a grip traction test (p = 0.0002). This model is well suited to studying the pathogenesis of PHVD.
Animals↗
Effects of hypothermia on energy metabolism in Mammalian central nervous system.
This review analyzes, in some depth, results of studies on the effect of lowered temperatures on cerebral energy metabolism in animals under normal conditions and in some selected pathologic situations. In sedated and paralyzed mammals, acute uncomplicated 0.5- to 3-h hypothermia decreases the global cerebral metabolic rate for glucose (CMR(glc)) and oxygen (CMRo(2)) but maintains a slightly better energy level, which indicates that ATP breakdown is reduced more than its synthesis. Intracellular alkalinization stimulates glycolysis and independently enhances energy generation. Lowering of temperature during hypoxia-ischemia slows the rate of glucose, phosphocreatine, and ATP breakdown and lactate and inorganic phosphate formation, and improves recovery of energetic parameters during reperfusion. Mild hypothermia of 12 to 24-h duration after normothermic hypoxic-ischemic insults seems to prevent or ameliorate secondary failures in energy parameters. The authors conclude that lowered head temperatures help to protect and maintain normal CNS function by preserving brain ATP supply and level. Hypothermia may thus prove a promising avenue in the treatment of stroke and trauma and, in particular, of perinatal brain injury.
Animals↗
Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy.
OBJECTIVE: Treatment of posthemorrhagic ventricular dilation in premature infants is fraught with failures and complications. We have piloted a new treatment aimed at removing intraventricular blood and the cytokines associated with hydrocephalus. METHODS: Twenty-four infants were enrolled with ventricular width enlarged to 4 mm over the 97th centile after a large intraventricular hemorrhage. Sixteen had parenchymal brain lesions before treatment. Median gestation was 28 weeks, and birth weight was 1150 g. At a median postnatal age of 17 days, 2 ventricular catheters (1 right frontal, 1 left occipital) were inserted with 13 infants also having a reservoir frontally. Tissue plasminogen activator 0.5 mg/kg was given intraventricularly 8 hours before the ventricles were irrigated with artificial cerebrospinal fluid at 20 mL/h for a median of 72 hours. RESULTS: Seventeen of 23 survivors (74%) did not require a ventriculoperitoneal shunt. One infant (of 23 weeks' gestation) died. Two infants developed reservoir-associated infection, and 2 infants had a second intraventricular hemorrhage. Of the 19 survivors aged >12 months postterm, 8 were normal, 7 (37%) had single disability, and 4 (21%) had multiple disabilities. CONCLUSIONS: Shunt surgery was reduced compared with historical controls with similar treatment criteria. Mortality and single and multiple disability rates all showed downward trends. Reducing pressure, free iron, and proinflammatory and profibrotic cytokines may reduce periventricular brain damage and permanent hydrocephalus. Additional advances will require a controlled trial and better knowledge of the mechanisms of hydrocephalus.
Brain Damage, Chronic↗
Clinical trials of treatments after perinatal asphyxia.
Following critical hypoxia-ischemia during labor and delivery, there is a window of therapeutic opportunity during hypoxic-ischemic encephalopathy. Meta-analysis of three randomized trials of prophylactic barbiturate therapy for neonatal hypoxic-ischemic encephalopathy showed no significant effect on death or disability. One randomized trial of allopurinol showed short-term benefits but was too small to test death or disability. No adequate trials of dexamethasone, calcium channel blockers, or magnesium sulphate have yet been completed, but pilot studies in infants have shown the cardiovascular risks of magnesium sulphate and calcium channel blockers. There is considerable evidence from animal studies that posthypoxic mild hypothermia reduces brain injury. One small randomized trial of mild hypothermia found no adverse effects but was too small to examine death or disability. One large randomized trial of selective head cooling has finished recruitment and a number of large trials of systemic mild hypothermia are ongoing. As time is critical with post-hypoxic interventions, the delay involved in obtaining informed parental consent for such trials might obscure a clinically important therapeutic effect.
Anticonvulsants↗
Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets.
OBJECTIVE: Selective head cooling (SHC) combined with mild body cooling is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischemic encephalopathy. It is proposed that SHC enables local hypothermic neuroprotection while minimizing the deleterious side effects of systemic hypothermia. However, there is little evidence that it is possible to cool the brain more than the body for a prolonged period of time. The aim of this study was to examine whether the brain (T(deep brain)) could be cooled to below the rectal temperature (T(rectal)) in our piglet hypoxia ischemia (HI) model for a period of 24 hours, using a head-cooling cap. METHODS: Eight anesthetized piglets (median age: 15 hours) had subdural and intracerebral basal ganglia temperature probes inserted. After a 45-minute global HI insult (known to produce permanent brain damage), SHC using a cap perfused with cold water (5 degrees C-24 degrees C) combined with overhead body heating to maintain T(rectal) at 34 to 35 degrees C was performed for 24 hours. RESULTS: The piglets were cooled to a median T(rectal) of 35.0 degrees C (interquartile range [IQR]: 34.7-35.3) for 24 hours. During this time, the median T(deep brain) was 31.4 degrees C (IQR: 30 degrees C-32.2 degrees C), with a median T(rectal) to T(deep brain) gradient of 3.4 degrees C (IQR: 2.7 degrees C-4.8 degrees C). At the end of the cooling period, this gradient was still maintained at a median of 3.3 degrees C (IQR: 2.9 degrees C-3.7 degrees C). The ability to obtain the gradient was not influenced by the size of the piglet (1300-1840 g). Cap cooling lowered scalp temperature (T(scalp)) to a median of 24.9 degrees C (IQR: 22.2 degrees C-29.2 degrees C) and subdural temperature to a median of 28.1 degrees C (IQR: 25.8 degrees C-29.5 degrees C) but did not result in either skin injury or superficial brain hemorrhage. There was no clinically useful correlation between T(scalp) and T(deep brain) or between T(scalp) and T(subdural). CONCLUSIONS: This study using our piglet HI model shows that it is possible by means of a head-cooling cap to cool the brain more than the body for a 24-hour period while keeping the core temperature mildly hypothermic. However, we were unable to predict temperatures inside the brain using surface temperature probes on the head.
Animals↗
Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
BACKGROUND: Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS: 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS: In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION: These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.
Body Temperature↗
Non-protein-bound iron in brain interstitium of newborn pigs after hypoxia.
Oxidative damage is implied in perinatal hypoxic-ischemic brain injury, most importantly in white matter. Nonprotein-bound iron (NPBI) catalyzes the formation of toxic hydroxyl radicals. We measured the extracellular level of NPBI through microdialysis in the cortex, striatum, and periventricular white matter before, during and after severe hypoxia in newborn pigs. NPBI was analyzed by a new spectrophotometric method in which ferrous iron is chelated by bathophenanthroline. NPBI was present in all brain areas under baseline conditions and increased in white matter from 0.97 (0.69) to 2.75 (1.85) micromol/l (not corrected for recovery rate) during early reoxygenation. NPBI may contribute to oxidative injury after perinatal hypoxic insults.
Animals↗