Brain volumes and functional outcomes in children without cerebral palsy after therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

AIM: To investigate whether brain volumes were reduced in children aged 6 to 8 years without cerebral palsy, who underwent therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (patients), and matched controls, and to examine the relation between subcortical volumes and functional outcome. METHOD: We measured regional brain volumes in 31 patients and 32 controls (median age 7 years and 7 years 2 months respectively) from T1-weighted magnetic resonance imaging (MRI). We assessed cognition using the Wechsler Intelligence Scales for Children, Fourth Edition and motor ability using the Movement Assessment Battery for Children, Second Edition (MABC-2). RESULTS: Patients had lower volume of whole-brain grey matter, white matter, pallidi, hippocampi, and thalami than controls (false discovery rate-corrected p < 0.05). Differences in subcortical grey-matter volumes were not independent of total brain volume (TBV). In patients, hippocampal and thalamic volumes correlated with full-scale IQ (hippocampi, r = 0.477, p = 0.010; thalami, r = 0.452, p = 0.016) and MABC-2 total score (hippocampi, r = 0.526, p = 0.004; thalami, r = 0.505, p = 0.006) independent of age, sex, and TBV. No significant correlations were found in controls. In patients, cortical injury on neonatal MRI was associated with reduced volumes of hippocampi (p = 0.001), thalami (p = 0.002), grey matter (p = 0.015), and white matter (p = 0.013). INTERPRETATION: Children who underwent therapeutic hypothermia have reduced whole-brain grey and white-matter volumes, with associations between hippocampal and thalamic volumes and functional outcomes.

Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy.

AIM: To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. METHOD: Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. RESULTS: More cases than controls had mammillary body abnormalities (34% vs 0%; p < 0.001). Cases with abnormal mammillary bodies had lower processing speed (p = 0.016) and full-scale IQ (p = 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p < 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p = 0.016; right p = 0.004) and increased radial diffusivity in the right MTT (p = 0.004) compared with cases without mammillary body abnormalities. INTERPRETATION: Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. WHAT THIS PAPER ADDS: Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.

Deleterious Effect of Crossfostering in Rat Pups on Hypoxic-Ischaemic Injury Tolerance and Hypothermic Neuroprotection.

We study the effect of hypothermia (HT) following hypoxic-ischaemic (HI) brain injury in postnatal day 7 (P7) rats. In 2015, new European Union animal transport regulations prompted a change in practice at the breeding facility, which henceforth crossfostered P3 litters to P8 older lactating dams prior to transportation. It is generally assumed that crossfostering does not significantly affect the experimental results. The aim of this study was to examine whether crossfostering affects our model consistency by modifying injury susceptibility and hypothermic neuroprotection. We analysed 219 pups from 11 experiments conducted between 2013 and 2015: 73 non-crossfostered and 146 crossfostered pups. At P7, all pups underwent unilateral common carotid artery ligation followed by 50 min of hypoxia (8% O2, 36°C). Immediately after this mild insult, the pups were randomized to post-insult normothermia or HT treatment. Pups were culled at P14. Injury was assessed by area loss of the ipsilateral hemisphere and histopathology scoring of the hippocampus, cortex, thalamus, and basal ganglia. Crossfostered pups had double the injury compared to non-crossfostered pups irrespective of the treatment group. Hypothermic neuroprotection was statistically significant, but with a smaller and less consistent effect in crossfostered pups (relative neuroprotection 16% vs. 31% in non-crossfostered). These results demonstrate hypothermic neuroprotection following a mild HI insult. A representative subset of 41 animals was also assessed for evidence of microglial reactivity; however, no detectable difference in microglial reactivity was observed between any of the groups. In conclusion, crossfostering alters outcomes in our established model through reduced insult tolerance and variable neuroprotection. Crossfostering as a common breeding practice is a largely unexplored variable in animal research that may result in invalid research conclusions if inadequately adjusted for by larger group sizes. As a result, crossfostering is likely to be inconsistent with the principles of replacement, reduction, and refinement.

Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth?

Infants with moderate to severe neonatal encephalopathy (NE) benefit significantly from therapeutic hypothermia, with reduced risk of death or disability. However, the need for therapeutic hypothermia for infants with milder NE remains unclear. It has been suggested that these infants should not be offered therapeutic hypothermia as they may not be at risk for adverse neurodevelopmental outcome and that the balance of risk against potential benefit is unknown. Several key questions need to be answered including first, whether one can define NE in the first 6 h after birth so as to accurately distinguish infants with brain injury who may be at risk for adverse neurodevelopmental consequences. Second, will treatment of infants with mild NE with therapeutic hypothermia improve or even worsen neurological outcomes? Although alternate treatment protocols for mild NE may be feasible, the use of the current approach combined with rigorous avoidance of hyperthermia and initiation of hypothermia as early as possible after birth may promote optimal outcomes. Animal experimental data support the potential for greater benefit for mild HIE compared with moderate to severe HIE. This review will summarize current knowledge of mild NE and the challenges to a trial in this population.

Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy.

PURPOSE OF REVIEW: Therapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research in to ways to further improve neurologic outcomes. RECENT FINDINGS: Recent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed. In conclusion, recent studies suggest that current protocols for therapeutic hypothermia are near-optimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.

Attention and visuo-spatial function in children without cerebral palsy who were cooled for neonatal encephalopathy: a case-control study.

Objectives: Dorsal-stream functions are vulnerable to early brain injury associated with neonatal encephalopathy (NE) following perinatal asphyxia, even in children not developing cerebral palsy (CP). Since therapeutic hypothermia (TH) became the standard treatment for NE, the incidence of CP is reduced but the impact on dorsal-stream functions is unknown. We aimed to compare dorsal-stream functions in TH-treated survivors of NE, without CP, with those of matched controls. Methods: We administered tests of dorsal-stream function to 29 case children aged 6-to-8 years treated with TH for NE and without CP, and 20 age, sex and social class matched controls. We used the Conner's Continuous Performance Test (CPT) 2nd Edition to assess attentiveness, based upon Hit Reaction Time (HRT) percentile score and HRT standard error percentile, the CPT HRT block change measure to assess sustained attention and the NEPSY-II block construction and arrows tests to assess visuo-spatial performance and mental rotation. Results: Case children performed significantly worse than controls on measures of attention and visuo-spatial function. Conclusions: Children given TH treatment for NE can have subtle attention difficulties with slower reaction times and reduced visuo-spatial processing. These findings illustrate the continued vulnerability of dorsal-stream functions following NE despite the use of TH.

Hypothermia Is Neuroprotective after Severe Hypoxic-Ischaemic Brain Injury in Neonatal Rats Pre-Exposed to PAM3CSK4.

BACKGROUND: Preclinical research on the neuroprotective effect of hypothermia (HT) after perinatal asphyxia has shown variable results, depending on comorbidities and insult severity. Exposure to inflammation increases vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury, and could be one explanation for those neonates whose injury is unexpectedly severe. Gram-negative type inflammatory exposure by lipopolysaccharide administration prior to a mild HI insult results in moderate brain injury, and hypothermic neuroprotection is negated. However, the neuroprotective effect of HT is fully maintained after gram-positive type inflammatory exposure by PAM3CSK4 (PAM) pre-administration in the same HI model. Whether HT is neuroprotective in severe brain injury with gram-positive inflammatory pre-exposure has not been investigated. METHODS: 59 seven-day-old rat pups were subjected to a unilateral HI insult, with left carotid artery ligation followed by 90-min hypoxia (8% O2 at Trectal 36°C). An additional 196 pups received intraperitoneal 0.9% saline (control) or PAM1 mg/kg, 8 h before undergoing the same HI insult. After randomisation to 5 h normothermia (NT37°C) or HT32°C, pups survived 1 week before they were sacrificed by perfusion fixation. Brains were harvested for hemispheric and hippocampal area loss analyses at postnatal day 14, as well as immunostaining for neuron count in the HIP CA1 region. RESULTS: Normothermic PAM animals (PAM-NT) had a comparable median area loss (hemispheric: 60% [95% CI 33-66]; hippocampal: 61% [95% CI 29-67]) to vehicle animals (Veh-NT) (hemispheric: 58% [95% CI 11-64]; hippocampal: 60% [95% CI 19-68]), which is defined as severe brain injury. Furthermore, mortality was low and similar in the two groups (Veh-NT 4.5% vs. PAM-NT 6.6%). HT reduced hemispheric and hippocampal injury in the Veh group by 13 and 28%, respectively (hemispheric: p = 0.048; hippocampal: p = 0.042). HT also provided neuroprotection in the PAM group, reducing hemispheric injury by 22% (p = 0.03) and hippocampal injury by 37% (p = 0.027). CONCLUSION: In these experiments with severe brain injury, Toll-like receptor-2 triggering prior to HI injury does not have an additive injurious effect, and there is a small but significant neuroprotective effect of HT. HT appears to be neuroprotective over a continuum of injury severity in this model, and the effect size tapers off with increasing area loss. Our results indicate that gram-positive inflammatory exposure prior to HI injury does not negate the neuroprotective effect of HT in severe brain injury.

Rectal temperature in the first five hours after hypoxia-ischemia critically affects neuropathological outcomes in neonatal rats.

BackgroundHyperthermia after hypoxia-ischemia (HI) in newborn infants is associated with worse neurological outcomes. Loss of thermoregulation may also be associated with greater injury.MethodsIn the postnatal-day 7 (P7) rat, the effect of 5 h of graded hyperthermia (38 °C or 39 °C) immediately after unilateral HI was compared with normothermia (NT, 37 °C) and therapeutic hypothermia (TH, 32 °C). Early (negative geotaxis) and late (staircase test) behavioral testing was performed, as well as neuropathology scoring in adulthood. Separately, P7 rats were exposed to HI, and individual nesting temperatures were monitored before analysis of neuropathology at P14.ResultsMortality increased as temperature was increased from 38 °C (0%) to 39 °C (50%) after HI. Hyperthermia also resulted in early behavioral deficits compared with NT. In adulthood, pathology scores in the thalamus, basal ganglia, cortex, and hippocampus increased as post-hypoxic temperature increased above NT. Significant global neuroprotection was seen in the TH group. However, no significant difference was seen between HI groups in the staircase test. One hour after HI, the core temperature of pups was inversely correlated with global pathology scores at P14.ConclusionEarly temperature is a significant determinant of injury after experimental HI. Spontaneous decreases in core temperature after HI may confound neuroprotection studies.

Effects of hypothermia for perinatal asphyxia on childhood outcomes.

BACKGROUND: In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benefits. METHODS: We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher. RESULTS: A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P=0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P=0.03) and the risk of moderate or severe disability (22% vs. 37%, P=0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children's health status and in results on 10 of 11 psychometric tests. CONCLUSIONS: Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood. (Funded by the United Kingdom Medical Research Council and others; TOBY ClinicalTrials.gov number, NCT01092637.).

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent.

Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, early-onset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. Seven-day-old Wistar rats (n = 178) were subjected to intraperitoneal injections of PAM3CSK4 (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-h delay, the left carotid artery was ligated followed by 50 min of hypoxia (8% O2) at a rectal temperature of 36°C. Pups received a 5-h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the insult. Brains were harvested after 7 days' survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM3CSK4-injected animals showed significantly more brain injury than vehicle animals (p = 0.014). Compared to NT, HT significantly reduced injury in the PAM3CSK4-injected animals, with reduced area loss (p < 0.001), reduced microglial activation (p = 0.006), and increased neuronal rescue in the CA1 region (p < 0.001). Experimental induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to HI injury. HT was highly neuroprotective after the PAM3CSK4-triggered injury, suggesting HT may be neuroprotective in the presence of a gram-positive infection. These results are in strong contrast to LPS studies where HT is not neuroprotective.

Amplitude-Integrated Electroencephalography Improves the Identification of Infants with Encephalopathy for Therapeutic Hypothermia and Predicts Neurodevelopmental Outcomes at 2 Years of Age.

OBJECTIVES: To examine whether using an amplitude-integrated electroencephalography (aEEG) severity pattern as an entry criterion for therapeutic hypothermia better selects infants with hypoxic-ischemic encephalopathy and to assess the time-to-normal trace for aEEG and magnetic resonance imaging (MRI) lesion load as 24-month outcome predictors. STUDY DESIGN: Forty-seven infants meeting Norwegian therapeutic hypothermia guidelines were enrolled prospectively. Eight-channel EEG/aEEG was recorded from 6 hours until after rewarming, and read after discharge. Neonatal MRI brain scans were scored for summated (range 0-11) regional lesion load. A poor outcome at 2 years was defined as death or a Bayley Scales of Infant-Toddler Development cognitive or motor composite score of <85 or severe hearing or visual loss. RESULTS: Three severity groups were defined from the initial aEEG; continuous normal voltage (CNV; n = 15), discontinuous normal voltage (DNV; n = 18), and a severe aEEG voltage pattern (SEVP; n = 14). Any seizure occurrence was 7% CNV, 50% DNV, and 100% SEVP. Infants with SEVP with poor vs good outcome had a significantly longer median (IQR) time-to-normal trace: 58 hours (9-79) vs 18 hours (12-19) and higher MRI lesion load: 10 (3-10) vs 2 (1-5). A poor outcome was noted in 3 of 15 infants with CNV, 4 of 18 infants with DNV, and 8 of 14 infants with SEVP. Using multiple stepwise linear regression analyses including only infants with abnormal aEEG (DNV and SEVP), MRI lesion load significantly predicted cognitive and motor scores. For the SEVP group alone, time-to-normal trace was a stronger outcome predictor than MRI score. No variable predicted outcome in infants with CNV. CONCLUSIONS: Selection of infants with encephalopathy for therapeutic hypothermia after perinatal asphyxia may be improved by including only infants with an early moderate or severely depressed background aEEG trace.

Reduced infancy and childhood epilepsy following hypothermia-treated neonatal encephalopathy.

OBJECTIVE: To investigate what proportion of a regional cohort of cooled infants with neonatal encephalopathy develop epilepsy (determined by the International League Against Epilepsy [ILAE] definition and the number of antiepileptic drugs [AEDs]) up to 8 years of age. METHODS: From 2006-2013, 151 infants with perinatal asphyxia underwent 72 h cooling. Clinical and amplitude-integrated electroencepalography (aEEG) with single-channel EEG-verified neonatal seizures were treated with AEDs. Brain magnetic resonance imaging (MRI) was assessed using a 0-11 severity score. Postneonatal seizures, epilepsy rates, and AED treatments were documented. One hundred thirty-four survivors were assessed at 18-24 months; adverse outcome was defined as death or Bayley III composite Cognition/Language or Motor scores <85 and/or severe cerebral palsy or severely reduced vision/hearing. Epilepsy rates in 103 children age 4-8 years were also documented. RESULTS: aEEG confirmed seizures occurred precooling in 77 (57%) 151 of neonates; 48% had seizures during and/or after cooling and received AEDs. Only one infant was discharged on AEDs. At 18-24 months, one third of infants had an adverse outcome including 11% mortality. At 2 years, 8 (6%) infants had an epilepsy diagnosis (ILAE definition), of whom 3 (2%) received AEDs. Of the 103 4- to 8-year-olds, 14 (13%) had developed epilepsy, with 7 (7%) receiving AEDs. Infants/children on AEDs had higher MRI scores than those not on AEDs (median [interquartile range] 9 [8-11] vs. 2 [0-4]) and poorer outcomes. Nine (64%) of 14 children with epilepsy had cerebral palsy compared to 13 (11%) of 120 without epilepsy, and 10 (71%) of 14 children with epilepsy had adverse outcomes versus 23 (19%) of 120 survivors without epilepsy. The number of different AEDs given to control neonatal seizures, aEEG severity precooling, and MRI scores predicted childhood epilepsy. SIGNIFICANCE: We report, in a regional cohort of infants cooled for perinatal asphyxia, 6% with epilepsy at 2 years (2% on AEDs) increasing to 13% (7% on AEDs) at early school age. These AED rates are much lower than those reported in the cooling trials, even with adjusting for our cohort's milder asphyxia. Long-term follow-up is needed to document final epilepsy rates.

Therapeutic hypothermia translates from ancient history in to practice.

Acute postasphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a "dream revisited". In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 y ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short "latent" phase, typically lasting ~6 h, only to die hours to days later during a "secondary" deterioration phase characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to midchildhood.

Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury.

INTRODUCTION: Bacterial lipopolysaccharide (LPS) injection prior to hypoxia-ischaemia significantly increases hypoxia-ischaemic brain injury in 7-day-old (P7) rats. In addition, therapeutic hypothermia (HT) is not neuroprotective in this setting. However, the mechanistic aspects of this therapeutic failure have yet to be elucidated. This study was designed to investigate the underlying cellular mechanisms in this double-hit model of infection-sensitised hypoxia-ischaemic brain injury. MATERIAL AND METHODS: P7 rat pups were injected with either vehicle or LPS, and after a 4-hour delay were exposed to left carotid ligation followed by global hypoxia inducing a unilateral stroke-like hypoxia-ischaemic injury. Pups were randomised to the following treatments: (1) vehicle-treated pups receiving normothermia treatment (NT) (Veh-NT; n = 40), (2) LPS-treated pups receiving NT treatment (LPS-NT; n = 40), (3) vehicle-treated pups receiving HT treatment (Veh-HT; n = 38) and (4) LPS-treated pups receiving HT treatment (LPS-HT; n = 35). On postnatal day 8 or 14, Western blot analysis or immunohistochemistry was performed to examine neuronal death, apoptosis, astrogliosis and microglial activation. RESULTS: LPS sensitisation prior to hypoxia-ischaemia significantly exacerbated apoptotic neuronal loss. NeuN, a neuronal biomarker, was significantly reduced in the LPS-NT and LPS-HT groups (p = 0.008). Caspase-3 activation was significantly increased in the LPS-sensitised groups (p < 0.001). Additionally, a significant increase in astrogliosis (glial fibrillary acidic expression, p < 0.001) was seen, as well as a trend towards increased microglial activation (Iba 1 expression, p = 0.051) in LPS-sensitised animals. Treatment with HT did not counteract these changes. CONCLUSION: LPS-sensitised hypoxia-ischaemic brain injury in newborn rats is mediated through neuronal death, apoptosis, astrogliosis and microglial activation. In this double-hit model, treatment with HT does not ameliorate these changes.

Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood.

BACKGROUND: We previously reported that combining immediate hypothermia with immediate or 2 h delayed inhalation of an inert gas, xenon, gave additive neuroprotection in rats after a hypoxic-ischemic insult, compared to hypothermia alone. Defining the therapeutic time window for this new combined intervention is crucial in clinical practice when immediate treatment is not always feasible. The aim of this study is to investigate whether combined hypothermia and xenon still provide neuroprotection in rats after a 5 h delay for both hypothermia and xenon. METHODS: Seven-day-old Wistar rat pups underwent a unilateral hypoxic-ischemic insult. Pups received 5 h of treatment starting 5 h after the insult randomized between normothermia, hypothermia, or hypothermia with 50% xenon. Surviving pups were tested for fine motor function through weeks 8-10 before being euthanized at week 11. Their hemispheric and hippocampal areas were assessed. RESULTS: Both delayed hypothermia-xenon and hypothermia-only treated groups had significantly less brain tissue loss than those which underwent normothermia. The functional performance after 1 wk and adulthood was significantly better after hypothermia-xenon treatment as compared to the hypothermia-only or normothermia groups. CONCLUSION: Adding 50% xenon to 5 h delayed hypothermia significantly improved functional outcome as compared to delayed hypothermia alone despite similar reductions in brain area.

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

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 (Trectal) 38.5 °C) or minimal HT (Trectal 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 Trectal was 37.0 ± 0.2 °C, and Tdeep brain and Tsuperficial brain were 35.0 ± 1.1 °C and 31.5 ± 1.6 °C, respectively, with stable Tbrain 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.

The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval.

BACKGROUND: Therapeutic hypothermia is the standard of care after perinatal asphyxia. Preclinical studies show 50% xenon improves outcome, if started early. METHODS: During a 32-patient study randomized between hypothermia only and hypothermia with xenon, 5 neonates were given xenon during retrieval using a closed-circuit incubator-mounted system. RESULTS: Without xenon availability during retrieval, 50% of eligible infants exceeded the 5-hour treatment window. With the transportable system, 100% were recruited. Xenon delivery lasted 55 to 120 minutes, using 174 mL/h (117.5-193.2) (median [interquartile range]), after circuit priming (1300 mL). CONCLUSIONS: Xenon delivery during ambulance retrieval was feasible, reduced starting delays, and used very little gas.

Respiratory sinus arrhythmia stabilizes mean arterial blood pressure at high-frequency interval in healthy humans.

PURPOSE: Arterial blood pressure variations are an independent risk factor for end organ failure. Respiratory sinus arrhythmia (RSA) is a sign of a healthy cardiovascular system. However, whether RSA counteracts arterial blood pressure variations during the respiratory cycle remains controversial. We restricted normal RSA with non-invasive intermittent positive pressure ventilation (IPPV) to test the hypothesis that RSA normally functions to stabilize mean arterial blood pressure. METHODS: Ten young volunteers were investigated during metronome-paced breathing and IPPV. Heart rate (ECG), mean arterial blood pressure and left stroke volume (finger arterial pressure curve) and right stroke volume (pulsed ultrasound Doppler) were recorded, while systemic and pulmonary blood flow were calculated beat-by-beat. Respiratory variations (high-frequency power, 0.15-0.40 Hz) in cardiovascular variables were estimated by spectral analysis. Phase angles and correlation were calculated by cross-spectral analysis. RESULTS: The magnitude of RSA was reduced from 4.9 bpm(2) (95% CI 3.0, 6.2) during metronome breathing to 2.8 bpm(2) (95% CI 1.1, 5.0) during IPPV (p = 0.03). Variations in mean arterial blood pressure were greater (2.3 mmHg(2) (95% CI 1.4, 3.9) during IPPV than during metronome breathing (1.0 mmHg(2) [95% CI 0.7, 1.3]) (p = 0.014). Respiratory variations in right and left stroke volumes were inversely related in the respiratory cycle during both metronome breathing and IPPV. CONCLUSIONS: RSA magnitude is lower and mean arterial blood pressure variability is greater during IPPV than during metronome breathing. We conclude that in healthy humans, RSA stabilizes mean arterial blood pressure at respiratory frequency.

Cooling neonates who do not fulfil the standard cooling criteria - short- and long-term outcomes.

AIM: Therapeutic hypothermia is effective and without serious adverse effects in term infants with hypoxic-ischaemic encephalopathy. It is unknown whether other neonatal patient groups could benefit from therapeutic hypothermia. Since 2006, our centre has offered cooling to infants fulfilling the standard cooling criteria, but also to those who did not. METHODS: Observational study with prospective data collection over a 6-year period in a regional cooling centre. Complications and outcome were compared between infants who were cooled not fulfilling the standard inclusion and exclusion criteria as set out in the CoolCap/TOBY protocol (n = 36) and infants who fulfilled the standard entry criteria (n = 129). RESULTS: 21.8% of cooled infants did not fulfil standard cooling entry criteria. This included infants cooled >6 postnatal hours, late preterm infants, and infants with postnatal collapse, major cranial haemorrhage, congenital cardiac disease and surgical conditions. Complication rates and long-term outcome did not differ significantly between the groups, apart from in infants with a major cranial haemorrhage, who had higher rates of coagulopathy and the worst outcome (80% death/disability). CONCLUSION: Cooling can be considered for infants with neonatal encephalopathy following postnatal collapse or preterm birth, those with underlying surgical or cardiac conditions, and infants starting cooling >6 postnatal hours.