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1.  Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic–ischemic pig model 
Autoregulation of cerebral perfusion is impaired in hypoxic–ischemic encephalopathy. We investigated whether cerebrovascular pressure reactivity (PRx), an element of cerebral autoregulation that is calculated as a moving correlation coefficient between averages of intracranial and mean arterial blood pressure (MABP) with values between −1 and +1, is impaired during and after a hypoxic–ischemic insult (HI) in newborn pigs. Associations between end-tidal CO2, seizures, neuropathology, and PRx were investigated. The effect of hypothermia (HT) and Xenon (Xe) on PRx was studied. Pigs were randomized to Sham, and after HI to normothermia (NT), HT, Xe or xenon hypothermia (XeHT). We defined PRx >0.2 as peak and negative PRx as preserved. Neuropathology scores after 72 hours of survival was grouped as ‘severe' or ‘mild.' Secondary PRx peak during recovery, predictive of severe neuropathology and associated with insult severity (P=0.05), was delayed in HT (11.5 hours) than in NT (6.5 hours) groups. Seizures were associated with impaired PRx in NT pigs (P=0.0002), but not in the HT/XeHT pigs. PRx was preserved during normocapnia and impaired during hypocapnia. Xenon abolished the secondary PRx peak, increased (mean (95% confidence interval (CI)) MABP (6.5 (3.8, 9.4) mm Hg) and cerebral perfusion pressure (5.9 (2.9, 8.9) mm Hg) and preserved the PRx (regression coefficient, −0.098 (95% CI (−0.18, −0.01)), independent of the insult severity.
PMCID: PMC3824173  PMID: 23899927
cerebrovascular pressure reactivity; hypothermia; hypoxia–ischemia; newborn; pig; xenon
2.  Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect? 
PLoS ONE  2014;9(10):e109845.
Breathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.
After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37°C, HT35°C, HT32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.
Immediate HT32°C (p = 0.042), but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.
Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.
PMCID: PMC4186877  PMID: 25286345
4.  Immediate hypothermia reduces cardiac troponin I following hypoxic-ischemic encephalopathy in newborn pigs 
Pediatric research  2011;70(4):352-356.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinically defined neurological condition following lack of oxygen and often associated with cardiac dysfunction in term infants. Therapeutic hypothermia after birth is neuroprotective in infants with HIE. However, it is not known whether hypothermia (HT) is also cardioprotective. Four newborn pigs were used in the pilot study and a further 18 newborn pigs (randomly assigned to 72h-normothermia (NT) or 24h-HT followed by 48h-NT) were subjected to global HIE insults. Serum cTnI was measured prior to and post the HIE insult. Blood pressure, inotropic support, blood gases and heart rate (HR) were recorded throughout. Cardiac pathology was assessed from histological sections. Cooling reduced serum cTnI levels significantly in HT pigs by 6h (NT, 1.36±0.67; HT 0.34±0.23 ng/ml, p=0.0009). After rewarming, from 24 to 30h post insult, HR and cTnI increased in the HT group; from HR[24h]=117±22 to HR[30h]=218±32 beats/minute (p=0.0002) and from cTnI[24h]=0.23±0.12 to cTnI[30h]=0.65±0.53ng/ml, (p=0.05). There were fewer ischemic lesions on cardiac examination (37%) in the HT group compared to the NT group (70%). Hypothermia (24h) pigs did not have the post-insult cTnI increase seen in NT treated pigs. There was a trend that HT improved cardiac pathology in this 3-day survival model.
PMCID: PMC3173864  PMID: 21691250
5.  Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data 
Objective To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age.
Design A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured.
Data sources Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts.
Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected.
Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months’ follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference −0.11, 95% CI −0.18 to −0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference −0.07, 95% CI −0.12 to −0.02), with a number needed to treat of 14 (95% CI 8 to 47).
Conclusions In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.
PMCID: PMC2819259  PMID: 20144981
6.  Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomised controlled trial 
Lancet Neurology  2010;9(1):39-45.
Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial.
In the TOBY trial hypoxic–ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571.
325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0·36, 95% CI 0·15–0·84; p=0·02), white matter (0·30, 0·12–0·77; p=0·01), and abnormal posterior limb of the internal capsule (0·38, 0·17–0·85; p=0·02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0·41, 0·18–0·91; p=0·03) and were more likely to have normal scans (2·81, 1·13–6·93; p=0·03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0·84 (0·74–0·94) in the cooled group and 0·81 (0·71–0·91) in the non-cooled group.
Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic–ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia.
UK Medical Research Council; UK Department of Health.
PMCID: PMC2795146  PMID: 19896902
7.  The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial 
BMC Pediatrics  2008;8:17.
A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants.
Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C have been reported. No complications were noted but the group sizes were too small to evaluate benefit.
TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".
Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2°C or to whole body cooling, with rectal temperature kept at 33–34°C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods.
Sample size
At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months.
Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited.
Primary outcome
Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of:
• Bayley mental developmental scale score less than 70
• Gross Motor Function Classification System Levels III – V
• Bilateral cortical visual impairments
Trial Registration
Current Controlled Trials ISRCTN89547571
PMCID: PMC2409316  PMID: 18447921
8.  Cerebral Doppler and misrepresentation of flow changes 
To determine whether cerebral blood flow velocity (CBFV) measurements were representative of cerebral blood flow (CBF) changes in pathological flow situations five newborn piglets were investigated. They underwent measurements of CBF by electromagnetic flowmetry on a modified common carotid artery where extracerebral branches were tied off simultaneously with Doppler recording either from the same precerebral or an intracerebral artery. The two methods agreed well within moderate carbon dioxide and blood pressure changes. During severe hypotension and hypertension Doppler overestimated CBF by 25-100%. During transfusion of infected or incompatible blood the two methods differed in opposite directions with Doppler reading from 30-200% of CBF. Transfusion of chilled blood caused CBFV to overestimate 15% and heated blood caused 20% underestimation. These results could be explained by diameter changes in response to variation in myogenic tone or vasoactive substances. CBFV measurements could be seriously misleading in severe clinical derangements where neonatal brain damage might occur.
PMCID: PMC1061092  PMID: 7979461
9.  Women Physiologists 
BMJ : British Medical Journal  1994;308(6937):1173-1174.
PMCID: PMC2540130
10.  Comparison of Bayley-2 and Bayley-3 scores at 18 months in term infants following neonatal encephalopathy and therapeutic hypothermia 
Neuroprotection trials for neonatal encephalopathy use moderate or severe disability as an outcome, with the Bayley Scales of Infant Development, Second Edition (Bayley-2) Index scores of <70 as part of the criteria. The Bayley Scales of Infant and Toddler, 3rd Development, Third Edition (Bayley-3) have superseded Bayley-2 and yield higher than expected scores in typically developing and high-risk infants. The aim of this study, therefore, was to compare Bayley-2 scores and Bayley-3 scores in term-born infants surviving neonatal encephalopathy treated with hypothermia.
Sixty-one term-born infants (37 males, 24 females; median gestational age at birth 40wks, range 36–42wks; median birthweight 3280g, range 2295–5050) following neonatal encephalopathy and hypothermia had contemporaneous assessment at 18 months using the Bayley-2 and Bayley-3.
The median Bayley-3 Cognitive Composite score was 7 points higher than the median Bayley-2 Mental Developmental Index (MDI) score and the median Bayley-3 Motor Composite score was 18 points higher than the median Bayley-2 Psychomotor Developmental Index (PDI) score. Ten children had a Bayley-2 MDI of <70; only three children had Bayley-3 combined Cognitive/Language scores of <70. Eleven children had Bayley-2 PDI scores of <70 and four had modified Bayley-3 Motor Composite scores of <70. Applying regression equations to Bayley-3 scores adjusted rates of severe delay to similar proportions found using Bayley-2 scores.
Fewer children were classified with severe delay using the Bayley-3 than the Bayley-2, which prohibits direct comparison of scores. Increased Bayley-3 cut-off thresholds for classifying severe disability are recommended when comparing studies in this clinical group using Bayley-2 scores.
PMCID: PMC4287199  PMID: 23927586

Results 1-10 (10)