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1.  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.
Background
Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial.
Objective
Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age.
Design/Methods
A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups.
Results
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.
Conclusions
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.
doi:10.1542/peds.2008-0456
PMCID: PMC2819143  PMID: 18829776
hypoxic-ischemic encephalopathy; whole-body hypothermia; safety; effectiveness
2.  Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study 
BMC Pediatrics  2012;12:45.
Background
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.
Methods/Design
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.
Discussion
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
NTR2529.
doi:10.1186/1471-2431-12-45
PMCID: PMC3358232  PMID: 22515424
Perinatal asphyxia, Therapeutic hypothermia; Pharmacokinetic research; Drug monitoring; Evidence based; Drug dosing; Guideline
3.  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.
doi:10.1007/s11940-012-0200-y
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
4.  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.
doi:10.1586/eog.10.7
PMCID: PMC2897079  PMID: 20625441
HIE; hyperthermia; hypothermia; hypoxic–ischemic encephalopathy; neonate; perinatal asphyxia
5.  Perinatal asphyxia 
Clinical Evidence  2007;2007:0320.
Introduction
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).
Results
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.
Conclusions
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
6.  Hepatic Dysfunction in Asphyxiated Neonates: Prospective Case-Controlled Study 
OBJECTIVE
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.
METHOD AND MATERIAL
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.
RESULTS
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.
CONCLUSION
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.
doi:10.4137/CMPed.S21426
PMCID: PMC4294631
birth asphyxia; hypoxic ischemic encephalopathy; hepatic dysfunction
7.  Passive cooling during transport of asphyxiated term newborns 
Objective
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.
Results
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.
Conclusions
Exclusive passive cooling for hypoxic-ischemic encephalopathy results in significantly earlier achievement of effective therapeutic hypothermia without significant adverse events.
doi:10.1038/jp.2012.138
PMCID: PMC4090084  PMID: 23154670
hypoxic-ischemic encephalopathy; therapeutic hypothermia; amplitude-integrated electroencephalography
8.  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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2013.10.067
PMCID: PMC4006934  PMID: 24332821
9.  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.
Summary
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
Funding
UK Medical Research Council; UK Department of Health.
doi:10.1016/S1474-4422(09)70295-9
PMCID: PMC2795146  PMID: 19896902
10.  Neonatal Neurobehavioral Abnormalities and MRI Brain Injury in Encephalopathic Newborns Treated With Hypothermia 
Early human development  2013;89(9):733-737.
Background
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.
Aim
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.
Results
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).
Conclusions
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.
doi:10.1016/j.earlhumdev.2013.05.006
PMCID: PMC3780358  PMID: 23787090
11.  Meta-analysis of efficacy of topiramate in migraine prophylaxis★ 
Neural Regeneration Research  2012;7(23):1806-1811.
OBJECTIVE:
To evaluate the treatment effects and safety of topiramate in migraine prophylaxis.
DATA RETRIEVAL:
We searched the Medline database, EMbase, Cochrane Library and China National Knowledge Infrastructure database for articles published between January 1995 and May 2011, using the key words “migraine”, “topiramate”, and “prophylaxis”.
SELECTION CRITERIA:
We selected randomized controlled trials of migraine patients, in which the experimental group was orally administered topiramate, and the control group was given placebo. Odds ratios (ORs) and mean differences (MDs) were calculated using a fixed effects model/random effects model. Quality evaluation and data extraction were performed independently by two researchers utilizing RevMan 5.0 software.
MAIN OUTCOME MEASURES:
Efficacy was recorded as the responder rate (response defined as at least a 50% reduction in average monthly migraine frequency) and change in mean monthly number of migraine days. Adverse events were recorded as the number of subjects exhibiting at least one adverse event.
RESULTS:
Eight randomized controlled trials were found to be appropriate, and had available data. The meta-analysis results revealed that topiramate (100 or 200 mg/d) was more effective than placebo in responder rate (OR = 2.97, 95% confidence interval (CI): 2.17–4.08, P < 0.01; OR = 2.35, 95%CI: 1.77–3.12, P < 0.01). Topiramate (100 mg/d) was more effective than placebo in terms of the change in mean monthly migraine days (MD: –1.14, 95%CI: –1.69 to –0.59, P < 0.01). The total incidence rate of adverse events for topiramate was higher than in the placebo group (P < 0.01), but most adverse events were mild to moderate.
CONCLUSION:
Overall, topiramate obtained good outcomes and safety in migraine prophylaxis.
doi:10.3969/j.issn.1673-5374.2012.23.007
PMCID: PMC4302531  PMID: 25624805
topiramate; migraine; prophylaxis; efficacy; meta-analysis; neural regeneration
12.  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.
doi:10.1016/j.pediatrneurol.2011.01.006
PMCID: PMC3092106  PMID: 21555055
Infant, newborn; Seizures; Electroencephalography; Magnetic resonance imaging
13.  Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine 
Neurology  2012;78(13):976-984.
Objective:
To assess the efficacy and safety of adding propranolol to topiramate in chronic migraine subjects inadequately controlled with topiramate alone.
Methods:
This was a double-blind, placebo-controlled, randomized clinical trial conducted through the National Institute of Neurological Disorders and Stroke Clinical Research Collaboration, expected to randomize 250 chronic migraine subjects inadequately controlled (≥10 headaches/month) with topiramate (50–100 mg/day) to either propranolol LA (long acting) (240 mg/day) or placebo. Primary outcome was 28-day moderate to severe headache rate reduction at 6 months (weeks 16 to 24) compared with baseline (weeks −4 to 0).
Results:
A planned interim analysis was performed after 48 sites randomized 171 subjects. The data and safety monitoring board recommended ending the trial after determining that it would be highly unlikely for the combination to result in a significant reduction in 28-day headache rate compared with topiramate alone if all 250 subjects were randomized. No safety concerns were identified. At study closure, 191 subjects were randomized. The 6-month reduction in moderate to severe 28-day headache rate and total 28-day headache rate for combination therapy vs topiramate alone was not significantly different: 4.0 vs 4.5 days (moderate to severe 28-day headache rate; p = 0.57) and 6.2 vs 6.1 days (total 28-day headache rate; p = 0.91).
Conclusions:
This study does not provide evidence that the addition of propranolol LA to topiramate adds benefit when chronic migraine is inadequately controlled with topiramate alone.
Classification of evidence:
This study provides Class II evidence that propranolol LA, added to topiramate, is ineffective in chronic migraine patients who fail topiramate monotherapy.
doi:10.1212/WNL.0b013e31824d5846
PMCID: PMC3310312  PMID: 22377815
14.  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.
Background
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.
Aims
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
Methods/Design
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.
Discussion
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
doi:10.1186/1745-6215-12-138
PMCID: PMC3127769  PMID: 21639927
15.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2011.09.018
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
16.  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.
Background/Aim:
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.
Results:
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.
Conclusions:
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
17.  A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy – are we there yet? 
BMC Pediatrics  2007;7:30.
Background
The objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.
Methods
The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL databases, reference lists of identified studies, and proceedings of the Pediatric Academic Societies were searched in July 2006. Randomized trials assessing the effect of therapeutic hypothermia by either selective head cooling or whole body cooling in term neonates were eligible for inclusion in the meta-analysis. The primary outcome was death or neurodevelopmental disability at ≥ 18 months.
Results
Five trials involving 552 neonates were included in the analysis. Cooling techniques and the definition and severity of neurodevelopmental disability differed between studies. Overall, there is evidence of a significant effect of therapeutic hypothermia on the primary composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20) as well as on the single outcomes of mortality (RR: 0.75, 95% CI: 0.59, 0.96) and neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98). Adverse effects include benign sinus bradycardia (RR: 7.42, 95% CI: 2.52, 21.87) and thrombocytopenia (RR: 1.47, 95% CI: 1.07, 2.03, NNH: 8) without deleterious consequences.
Conclusion
In general, therapeutic hypothermia seems to have a beneficial effect on the outcome of term neonates with moderate to severe hypoxic ischemic encephalopathy. Despite the methodological differences between trials, wide confidence intervals, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging. Further research is necessary to minimize the uncertainty regarding efficacy and safety of any specific technique of cooling for any specific population.
doi:10.1186/1471-2431-7-30
PMCID: PMC2031882  PMID: 17784966
18.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
IMPORTANCE
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
OBJECTIVE
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
DESIGN, SETTING, AND PARTICIPANTS
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
INTERVENTIONS
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
MAIN OUTCOMES AND MEASURES
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
RESULTS
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
CONCLUSIONS AND RELEVANCE
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
doi:10.1001/jama.2014.16058
PMCID: PMC4335311  PMID: 25536254
19.  Systematic Review and Meta-Analysis of Therapeutic Hypothermia in Animal Models of Spinal Cord Injury 
PLoS ONE  2013;8(8):e71317.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0071317
PMCID: PMC3739756  PMID: 23951131
20.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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; ClinicalTrials.gov number, NCT00005772.)
doi:10.1056/NEJMoa1112066
PMCID: PMC3459579  PMID: 22646631
21.  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.
doi:10.1136/bmj.c363
PMCID: PMC2819259  PMID: 20144981
22.  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.
Objective
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.
Results
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).
Conclusions
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.
doi:10.1016/j.jpeds.2012.06.042
PMCID: PMC3712522  PMID: 22871488
23.  The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial 
BMC Pediatrics  2008;8:17.
Background
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.
Methods/Design
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
doi:10.1186/1471-2431-8-17
PMCID: PMC2409316  PMID: 18447921
24.  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.
doi:10.1038/jp.2010.146
PMCID: PMC3552186  PMID: 21183927
hypothermia; hypoxic-ischemic encephalopathy; neonate; pharmacologic effect; physiology effect; rewarming
25.  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.
doi:10.1371/journal.pone.0047583
PMCID: PMC3471862  PMID: 23077646

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