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1.  Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study 
BMC Pediatrics  2012;12:45.
In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.
Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.
On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.
Trial registration
PMCID: PMC3358232  PMID: 22515424
Perinatal asphyxia, Therapeutic hypothermia; Pharmacokinetic research; Drug monitoring; Evidence based; Drug dosing; Guideline
2.  Hypothermia for hypoxic–ischemic encephalopathy 
Moderate to severe hypoxic–ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic–ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic–ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic–ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic–ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem.
PMCID: PMC2897079  PMID: 20625441
HIE; hyperthermia; hypothermia; hypoxic–ischemic encephalopathy; neonate; perinatal asphyxia
3.  Perinatal asphyxia 
BMJ Clinical Evidence  2007;2007:0320.
In resource-rich countries, the incidence of severe perinatal asphyxia (causing death or severe neurological impairment) is about 1/1000 live births. In resource-poor countries, perinatal asphyxia is probably much more common. Data from hospital-based studies in such settings suggest an incidence of 5–10/1000 live births.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in term or near-term newborns with perinatal asphyxia? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (prophylactic), antioxidants, calcium channel blockers, corticosteroids, fluid restriction, head and/or whole body hypothermia, hyperbaric oxygen treatment, hyperventilation, inotrope support, magnesium sulphate, mannitol, opiate antagonists, and resuscitation (in air versus higher concentrations of oxygen).
Key Points
Estimates of the incidence of perinatal asphyxia vary. In resource-rich countries, severe perinatal asphyxia (causing death or severe neurological impairment) is 1/1000 live births; in resource-poor countries, studies suggest an incidence of 5–10/1000 live births.
Limited evidence from three small, weak RCTs suggests that mortality may be lower in infants treated with antioxidants compared with placebo.
There is limited evidence that hypothermia reduces mortality and neurodevelopmental disability in infants with perinatal asphyxia.
Limited evidence from one small RCT suggests that a magnesium sulphate/dopamine combination may be more effective than no treatment in reducing a combined outcome of mortality, abnormal scans, and failure to feed.
Small RCTs with flawed methods suggest that anticonvulsants are of no benefit in reducing mortality or improving neurodevelopmental outcomes in term infants with perinatal asphyxia.
Resuscitation in air lowered mortality in infants with perinatal asphyxia compared with resuscitation in 100% oxygen. However, current clinical practice is to use 100% oxygen.
Limited evidence from a systematic review that reported problems with publication bias in the RCTs it identified suggests that hyperbaric oxygen treatment lowers rates of mortality and adverse neurological outcomes in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy. This treatment, although widely used in China, is not standard practice in other countries.
We don't know whether calcium channel blockers, corticosteroids, fluid restriction, hyperventilation, inotrope support, mannitol, or opiate antagonists are helpful in infants with perinatal asphyxia.
PMCID: PMC2943784  PMID: 19450354
4.  Therapeutic Hypothermia for Neonatal Encephalopathy 
Opinion statement
Neonatal Hypoxic-ischemic encephalopathy in full term infants has been associated with a high risk for morbidity and mortality. The patho-physiology of brain injury following hypoxia-ischemia, noted in preclinical models, is a cascade of events resulting from excitotoxic and oxidative injury culminating in cell death. Hypothermia has been noted to be protective by inhibiting various events in the cascade of injury. Major randomized clinical trials in neonatal HIE have demonstrated reduction in death and disability and continued safety and efficacy of neuroprotection in childhood. There is now clinical and imaging evidence for hypothermia as neuroprotection. Hypothermia should be offered to term infants with either severe acidosis at birth or resuscitation needing continued ventilation and evidence of either moderate or severe encephalopathy within 6 hours of birth. The target temperature should be 33° to 34 °C and duration of cooling should be 72 hours, as per the published trials. Rewarming should be slow, at 0.5 °C per hour. Infants should have serial neurological examinations during and at the end of cooling and at discharge. Multiorgan function should be supported and hypocarbia should be avoided during ventilator therapy. If available, the amplitude integrated EEG should be obtained prior to cooling and following rewarming. All infants should have magnetic resonance brain imaging studies within 1 to 2 weeks of age. Information from the neurological examination, aEEG and MRI studies will be helpful in discussing prognosis with parents. All infants should be followed for a minimum of 18 months to evaluate growth parameters and neurodevelopment al outcome.
PMCID: PMC3519960  PMID: 23007949
Therapeutic hypothermia; Neonatal encephalopathy; Term infants; Neonatal hypoxic-ischemic encephalopathy; Pathophysiology; Neurodevelopmental outcome; Neuroprotection; Head cooling; Whole body cooling; Randomized controlled trials; Knowledge gaps; Adjuvant therapies; Treatment
5.  Outcomes of Safety and Effectiveness in a Multicenter Randomized, Controlled Trial of Whole-Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
Pediatrics  2008;122(4):e791.
Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial.
Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age.
A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups.
Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non–central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5°C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories.
Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.
PMCID: PMC2819143  PMID: 18829776
hypoxic-ischemic encephalopathy; whole-body hypothermia; safety; effectiveness
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.  Hepatic Dysfunction in Asphyxiated Neonates: Prospective Case-Controlled Study 
This study was performed to determine the occurrence of hypoxic hepatitis in full-term neonates after perinatal asphyxia and to correlate between the rise in enzymes and severity of asphyxia with Apgar score and hypoxic ischemic encephalopathy (HIE) grading of the neonates.
This prospective case-controlled study was conducted in a tertiary-level hospital in India for a period of 12 months. The study group A comprised 70 newborns suffering from birth asphyxia, while 30 healthy neonates were included in group B (control). All biochemical parameters of liver function, ie, serum alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, serum albumin, bilirubin (total and direct), and international normalized ratio (INR), were measured on postnatal days 1, 3, and 10 in both study and control groups.
In group A, 22.8% newborns had severe (Apgar score 0–3), 47.1% had moderate (Apgar score 4–5), and 30% had mild (Apgar score 6–7) birth asphyxia at five minutes. In all, 14.28% babies were in HIE stage I, 25.73% babies were in HIE stage II, and 11.42% babies were in HIE stage III. The rest of the newborns, 48.57%, were normal. The prevalence of liver function impairment was seen in 42.85% of asphyxiated neonates. On day 1, ALT, AST, ALP, LDH, PT, and INR were significantly higher, and total protein and serum albumin were significantly lower in group A than in group B. However, ALT and AST correlated well with increasing severity of HIE score. On day 3, there was a rising trend observed in the concentration of mean LDH as HIE staging of neonates progressed from stage 0 to stage III, and among various HIE stages, the difference in LDH was statistically significant.
We concluded that AST, ALT at 24 hours, and LDH at 72 hours of animation can be a utilitarian diagnostic tool to differentiate asphyxiated neonates from non-asphyxiated neonates and to discover the severity of perinatal asphyxia because of easy accessibility and feasibility of tests. The outcomes of this survey would be useful for physicians who receive neonates for whom birth details are not easily documented as most of the time the referred newborn infants lack asphyxia history either because the attendants do not know clearly the whole birth history or it was an unattended delivery, or the referring health-care professional has not been observant because of legal threats. The neurological assessment also becomes difficult and inconclusive as ventilator treatment, sedative drugs, and anticonvulsant therapy would produce an evaluation of severity of hypoxic ischemic brain disease and neurological insult difficult.
PMCID: PMC4294631
birth asphyxia; hypoxic ischemic encephalopathy; hepatic dysfunction
8.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Study design
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
9.  Biomarkers for Severity of Neonatal Hypoxic-Ischemic Encephalopathy and Outcomes in Newborns Receiving Hypothermia Therapy 
The Journal of pediatrics  2013;164(3):468-74.e1.
To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes.
Study design
This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6–24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15–18 months.
Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6–24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6–24 hours were associated with abnormal neurological outcomes.
The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes.
PMCID: PMC4006934  PMID: 24332821
10.  Neonatal Neurobehavioral Abnormalities and MRI Brain Injury in Encephalopathic Newborns Treated With Hypothermia 
Early human development  2013;89(9):733-737.
Neonatal Encephalopathy (NE) is a prominent cause of infant mortality and neurodevelopmental disability. Hypothermia is an effective neuroprotective therapy for newborns with encephalopathy. Post-hypothermia functional-anatomical correlation between neonatal neurobehavioral abnormalities and brain injury findings on MRI in encephalopathic newborns has not been previously described.
To evaluate the relationship between neonatal neurobehavioral abnormalities and brain injury on magnetic resonance imaging (MRI) in encephalopathic newborns treated with therapeutic hypothermia.
Study Design
Neonates with hypoxic ischemic encephalopathy (HIE) referred for therapeutic hypothermia were prospectively enrolled in this observational study. Neurobehavioral functioning was assessed with the NICU Network Neurobehavioral Scale (NNNS) performed at target age 14 days. Brain injury was assessed by MRI at target age 7–10 days. NNNS scores were compared between infants with and without severe MRI injury.
Subjects & Outcome Measures
Sixty-eight term newborns (62% males) with moderate to severe encephalopathy underwent MRI at median 8 days (range 5–16) and NNNS at median 12 days of life (range 5–20). Fifteen (22%) had severe injury on MRI.
Overall Total Motor Abnormality Score and individual summary scores for Nonoptimal Reflexes and Asymmetry were higher, while Total NNNS Z-score across cognitive/behavioral domains was lower (reflecting poorer performance) in infants with compared to those without severe MRI injury (p<0.05).
Neonatal neurobehavioral abnormalities identified by the NNNS are associated with MRI brain injury in encephalopathic newborns post-hypothermia. The NNNS can provide an early functional assessment of structural brain injury in newborns, which may guide rehabilitative therapies in infants after perinatal brain injury.
PMCID: PMC3780358  PMID: 23787090
11.  Systematic Review and Meta-Analysis of Therapeutic Hypothermia in Animal Models of Spinal Cord Injury 
PLoS ONE  2013;8(8):e71317.
Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously.
In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group.
Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI −3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature.
Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies.
PMCID: PMC3739756  PMID: 23951131
12.  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
13.  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
14.  Combination Treatment of Hypothermia and Mesenchymal Stromal Cells Amplifies Neuroprotection in Primary Rat Neurons Exposed to Hypoxic-Ischemic-Like Injury In Vitro: Role of the Opioid System 
PLoS ONE  2012;7(10):e47583.
This study was designed to reveal the therapeutic regimen and mechanism of action underlying hypothermia treatment in combination with stem cell transplantation for ameliorating neonatal hypoxic-ischemic-like injury. Primary rat neurons were exposed to oxygen-glucose deprivation (OGD), which produced hypoxic-ischemic-like injury in vitro, then incubated at 25°C (severe hypothermia), 34°C (moderate hypothermia), and 37°C (normothermia) with or without subsequent co-culture with mesenchymal stromal cells (MSCs). Combination treatment of moderate hypothermia and MSCs significantly improved cell survival and mitochondrial activity after OGD exposure. The exposure of delta opioid human embryonic kidney cells (HEK293) to moderate hypothermia attenuated OGD-mediated cell alterations, which were much more pronounced in HEK293 cells overexpressing the delta opioid receptor. Further, the addition of delta opioid peptide to 34°C hypothermia and stem cell treatment in primary rat neurons showed synergistic neuroprotective effects against OGD which were significantly more robust than the dual combination of moderate hypothermia and MSCs, and were significantly reduced, but not completely abolished, by the opioid receptor antagonist naltrexone altogether implicating a ligand-receptor mechanism of neuroprotection. Further investigations into non-opioid therapeutic signaling pathways revealed growth factor mediation and anti-apoptotic function accompanying the observed therapeutic benefits. These results support combination therapy of hypothermia and stem cells for hypoxic-ischemic-like injury in vitro, which may have a direct impact on current clinical trials using stand-alone hypothermia or stem cells for treating neonatal encephalopathy.
PMCID: PMC3471862  PMID: 23077646
15.  Therapeutic hypothermia in asphyxiated neonates with hypoxic-ischemic encephalopathy: A single-center experience from its first application in Greece 
Hippokratia  2014;18(3):226-230.
Therapeutic hypothermia has become an established therapy in asphyxiated neonates with evidence of moderate/severe hypoxic-ischemic encephalopathy. Herein, we describe our recent experience with total body cooling in asphyxiated neonates, which is the first relevant report in Greece.
Patients and Methods:
The medical records of all asphyxiated newborns treated with therapeutic hypothermia in our center between September 2010 and October 2013 were retrospectively reviewed. We recorded data related to neonatal-perinatal characteristics, whole body cooling and outcome.
Twelve asphyxiated neonates [median gestational age 38 weeks (36-40)] received whole body cooling (rectal temperature 33.5 ± 0.5 oC for 72 hours) during the study period for moderate (n=3) and severe (n=9) hypoxic-ischemic encephalopathy. Cooling was passive in 4 and active in 8 (66.7%) cases. Therapeutic hypothermia was initiated at the median age of 5 hours (0.5-11) after birth. Seven neonates survived (58.3%) to hospital discharge. On follow-up (7-35 months), neurodevelopment outcome was normal in 1 case, while 3, 1 and 2 subjects had mild, moderate and severe impairment, respectively.
Our initial experience with whole body cooling supports its beneficial effect in asphyxiated neonates. This treatment should be offered in all centers involved in the care of such neonates using either simple means (passive cooling) or automated cooling devices. Hippokratia 2014; 18 (3): 226-230.
PMCID: PMC4309142
neonatal encephalopathy; neonatal care; perinatal asphyxia
16.  Passive cooling during transport of asphyxiated term newborns 
To evaluate the efficacy and safety of passive cooling during transport of asphyxiated newborns.
Study Design
Retrospective medical record review of newborns with perinatal asphyxia transported for hypothermia between July 2007 and June 2010.
Forty-three newborns were transported, 27 of whom were passively cooled. Twenty (74%) passively cooled newborns arrived with axillary temperature between 32.5 and 34.5 °C. One newborn (4%) arrived with a subtherapeutic temperature, and 6 (22%) had temperatures >34.5 °C. Time from birth to hypothermia was significantly shorter among passively cooled newborns compared with newborns not cooled (215 vs. 327 minutes, p<0.01), even though time from birth to arrival was similar (252 vs. 259 minutes, p=0.77). There were no significant adverse events related to passive cooling.
Exclusive passive cooling for hypoxic-ischemic encephalopathy results in significantly earlier achievement of effective therapeutic hypothermia without significant adverse events.
PMCID: PMC4090084  PMID: 23154670
hypoxic-ischemic encephalopathy; therapeutic hypothermia; amplitude-integrated electroencephalography
17.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.
In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.
Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80).
The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; number, NCT00005772.)
PMCID: PMC3459579  PMID: 22646631
18.  Therapeutic hypothermia in neonatal asphyxia 
Facts, Views & Vision in ObGyn  2012;4(2):133-139.
Hypoxic ischemic encephalopathy is a serious condition affecting newborn infants which can result in death and disability. There is now strong clinical evidence that moderate post-asphyxial total body cooling or hypothermia in full term neonates results in long-term neuroprotection, allowing us to proclaim this innovative therapy as “standard of care.” The treatment is a time-critical emergency and should be started within 6 hours after the insult. Such ­requires optimal collaboration among local hospitals, transport teams and the closest neonatal intensive care unit. The technique is only safe when applied according to published clinical trial protocols, and with admission of these patients to a neonatal intensive care unit. Future studies should be aimed at optimizing the onset, duration, and depth of hypothermia. Combination of hypothermia and drugs may further improve neuroprotection in asphyxiated full term neonates.
PMCID: PMC3987503  PMID: 24753900
Newborn; asphyxia; hypothermia; aEEG; HIE
19.  Short-Term Outcomes of Newborns with Perinatal Acidemia Who are Not Eligible for Systemic Hypothermia Therapy 
The Journal of pediatrics  2012;162(1):35-41.
To determine short-term outcomes of infants who had perinatal acidemia and were evaluated for hypothermia therapy but did not qualify based on a standardized neurologic examination.
Study design
Retrospective, single-site cohort study of inborn infants of ≥36 weeks gestation who had perinatal acidemia from October 2005-September 2008 and had a standardized neurologic examination performed by a certified neonatologist to assess eligibility for hypothermia therapy. An abnormal short-term nursery outcome was defined as death, seizures, brain magnetic resonance imaging consistent with hypoxic-ischemic encephalopathy, abnormal neurologic examination at discharge, gastrostomy tube feeding, or inability to nipple all feeds beyond the first week of age.
One hundred forty-four (0.3%) of 46 887 newborns with perinatal acidemia had a neurologic examination performed that was either normal (n = 29) or consistent with mild encephalopathy (1 or 2 abnormal categories; n = 60). Of the latter infants classified as having mild encephalopathy, 12 (20%) experienced an abnormal short-term outcome (feeding difficulties, n = 8; abnormal neurologic examination at discharge, n = 7; abnormal brain magnetic resonance imaging, n = 6; seizures, n = 5; gastrostomy, n = 1; or death, n = 1).
Twenty percent of newborns with perinatal acidemia and a neurologic examination that revealed only mild encephalopathy had abnormal short-term outcomes that could be attributed to the encephalopathy. Adjunctive tools or biomarkers for optimal assessment of infants with fetal acidemia for hypothermia therapy are needed.
PMCID: PMC3712522  PMID: 22871488
20.  Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in uganda: study protocol 
Trials  2011;12:138.
There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective.
Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine:
(i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles
(ii) The temperature profile of encephalopathic infants with standard care
(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome
(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age
Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months.
We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future.
Trial registration
Current controlled trials ISRCTN92213707
PMCID: PMC3127769  PMID: 21639927
21.  Physiologic and pharmacologic considerations for hypothermia therapy in neonates 
With mounting evidence that hypothermia is neuroprotective in newborns with hypoxic-ischemic encephalopathy (HIE), an increasing number of centers are offering this therapy. Hypothermia is associated with a wide range of physiologic changes affecting every organ system, and awareness of these effects is essential for optimum patient management. Lowering the core temperature also alters pharmacokinetic and pharmacodynamic properties of medications commonly used in asphyxiated neonates, necessitating close attention to drug efficacy and side effects. Rewarming introduces additional risks and challenges as the hypothermia-associated physiologic and pharmacologic changes are reversed. In this review we provide an organ system-based assessment of physiologic changes associated with hypothermia. We also summarize evidence from randomized controlled trials showing lack of serious adverse effects of moderate hypothermia therapy in term and near-term newborns with moderate-to-severe HIE. Finally, we review the effects of hypothermia on drug metabolism and clearance based on studies in animal models and human adults, and limited data from neonates.
PMCID: PMC3552186  PMID: 21183927
hypothermia; hypoxic-ischemic encephalopathy; neonate; pharmacologic effect; physiology effect; rewarming
22.  Electroencephalogram and Magnetic Resonance Imaging Comparison as a Predicting Factor for Neurodevelopmental Outcome in Hypoxic Ischemic Encephalopathy Infant Treated with Hypothermia 
Pediatric Reports  2014;6(3):5532.
Hypoxic-ischemic encephalopathy (HIE) is an important cause of acute neurological damage in newborns at (or near) term. Several trials in recent years have shown that moderate hypothermia by total body cooling or selective head is an effective intervention to reduce mortality and major disability in infants survived a perinatal hypoxic-ischemic attack. Follow-up in these patients is very important to establish neurodevelopmental outcome, and specific markers can lead us to detect predicting sign for good or poor outcome. We reported a few cases of newborn with HIE treated with hypothermia, in whom the comparison between electroencephalogram (EEG) and magnetic resonance imaging (MRI) represents the first marker for neurodevelopment outcome prediction. The continuous EEG monitoring showed a depressed EEG activity with diffuse burst depression in 7 patients. No epileptic abnormalities were registered. In 10 out of 20 patients no abnormalities of the background activity and no epileptic abnormalities were observed. We found that a depressed EEG activity during the first 72 h of life and a diffused alteration of basal ganglia at MRI were correlated with a poor neurodevelopmental outcome at 18 months of follow-up.
PMCID: PMC4292060  PMID: 25635216
hypothermia; neonates; magnetic resonance imaging; long term; electroencephalogram monitoring
23.  Selective head cooling for the treatment of neurologic complications of acute liver failure in a newborn with disseminated herpes infection 
SpringerPlus  2013;2:572.
Neurologic complications of pediatric acute liver failure (ALF) are a major determinant of outcome. Management of these complications, including increased intracranial pressure (ICP) is largely supportive. Although hypothermia is an effective treatment for perinatal asphyxia and is used to reduce ICP following traumatic brain injury, it has not been evaluated for neurologic complications of ALF in the newborn.
Case report.
We present a case of neonatal herpes simplex virus (HSV)-associated ALF with profound neurologic impairment and increased ICP. The patient was treated with selective head cooling, and monitored with transcranial doppler (TCD) studies of cerebral blood flow velocity, and electroencephalograms (EEG). The duration of head cooling was influenced by absent diastolic flow on TCDs, which subsequently improved during hypothermia. Continuous EEGs captured subclinical seizures, which improved with antiepileptic medications. Her death was attributed to a massive pulmonary hemorrhage and a hypoxemic cardiac arrest secondary to significant coagulopathy.
This case demonstrates that selective head cooling may attenuate increased ICP in neonatal encephalopathy, and that TCDs may guide management in the absence of invasive monitoring.
PMCID: PMC3825224  PMID: 24255865
Acute liver failure; Transcranial doppler; EEG; Neonate; Hypothermia
24.  Perinatal Events and Early MRI in Therapeutic Hypothermia 
The Journal of pediatrics  2010;158(3):360-365.
To compare the association between perinatal events and the pattern and extent of brain injury on early MRI in newborns with and without therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE).
Study design
We performed a cohort study of 35 treated and 25 non-treated neonates who underwent MRI. The injury patterns were defined a priori as: normal (N), watershed (WS) or basal ganglia/thalamus (BG/T) predominant, as well as a dichotomous outcome of moderate-to-severe versus mild-no injury.
Neonates with hypothermia had less extensive WS and BG/T injuries, and a greater proportion had normal imaging. Therapeutic hypothermia was associated with a decreased risk of both BG/T injury (RR 0.29, 95% CI 0.10-0.81, p = 0.01) and moderate-severe injury. Neonates with sentinel events showed a decrease in BG/T predominant injury and increase in normal imaging. All neonates with decreased fetal movements had injury, predominantly WS, regardless of therapeutic hypothermia.
These results validate reports of reduced brain injury following therapeutic hypothermia, and suggest that perinatal factors are important indicators of response to treatment.
PMCID: PMC3035732  PMID: 20965514
Neonatal; MRI; Hypoxia-ischemia; Hypothermia therapy
25.  Topiramate for the Treatment of Neonatal Seizures 
Pediatric neurology  2011;44(6):439-442.
Current therapeutic options for treatment of neonatal seizures, such as phenobarbital and phenytoin lack efficacy, and are potentially harmful to the developing brain. Topiramate appears to be effective as both an anti-seizure and neuroprotective agent in animal models of newborn brain injury. Though topiramate is commonly used as an add-on agent in newborns, its use in this population has not yet been reported. We performed a retrospective cohort study of clinical topiramate use in newborns with acute symptomatic seizures that were refractory to standard agents. In four of six identified newborns, there was apparent reduction or no further seizures, and none of the children experienced side effects that resulted in discontinuation of the drug, either during the hospital admission or after discharge home. Prospective studies evaluating the safety and efficacy of topiramate for both seizures and neuroprotection will be important to determine whether this medication deserves widespread use in clinical practice.
PMCID: PMC3092106  PMID: 21555055
Infant, newborn; Seizures; Electroencephalography; Magnetic resonance imaging

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