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Therapeutic Hypothermia for Newborns

Moderate induced hypothermia for newborns with hypoxic-ischemic encephalopathy
by

Young Byun

on 12 March 2015

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Transcript of Therapeutic Hypothermia for Newborns

Summary
DE
LAY
OVER
COOL
HYP
ERTHERMIA
HYPO
CARBIA
Don’t forget
THE COOL HIP HIPPO!!!
Does it work? - Yes, but it is no panacea
Is it safe? - Yes, under protocols with modest hypothermia
Who should be cooled? - Newborns who meet criteria for moderate -severe encephalopathy.
Historical Perspectives
Young S. Byun MD, FAAP
Pediatrix/Mednax, Dept of Neonatology
Winnie Palmer Hospital for Women & Babies

Disclosures
Relevant financial relationships
Nothing to disclose
Hephaestus
Obladen M., Lame from birth: early concepts of cerebral palsy. J Child Neurol, 2011, 26: 248
Pan
Satan
Painting by Mantegna 1465
for Newborns with Hypoxic
Ischemic Encephalopathy

Deformations have been attributed to supernatural causes since ancient times
4,000 year old Sumerian, Chaldean, and Babylonian incantations against the evil eye were translated from cuneiform writings. Pregnant women and neonates were believed to be particularly vulnerable and mothers hid their babies from the gaze of strangers and tried to protect themselves with amulets.
Do you know?

Which Greek God had Perinatal spastic hemiplegia?
Plato (4th century BC) was convinced that proper swaddling prevented limb deformities and ironically proposed a law
‘‘Do you wish us to go ahead despite the laughter and set forth laws to the effect that a pregnant woman must go for walks, and that when the child is born she must mold it like wax so long as it remains moist, swaddling it in clothes until it is two years old?’’
Attic tombstones 700-300 BC
“Difficult birth, in certain cases, is merely a symptom of deeper effects that influence the development of the fetus.”
-Sigmund Freud 1897
T1
Mild
Moderate
Severe
Day 3 – T1
Day 3 – ADC
Day 14 – T1
T1
Normal
Progression of Brain Injury
T1 weighted day # 1 DWI day # 1 MR Spectroscopy (lactate) day # 1
http://www.dailymail.co.uk/news/article-1243081/Babys-incredible-skull-cap-seeks-unravel-mysteries-autism.html
Whole body wrap - Criticool
Baby #1
1/14/2011
http://www.mtre.com/apage/23285.php
Francois Mauriceau, accoucheur in Paris, taught in his traite´ (first ed. 1668) ‘‘Its arms and legs should be extended and bound straight at the side of the body... It should be swaddled to give the small body a straight shape, which is the most decent and suitable for the human, and to accustom it to stand on its feet.’’ The cruel habit of tight swaddling persisted in many regions into present times.
“Sarah Parks . . . gave still-birth to a baby boy . . . A young doctor assisting the Parks’ regular physician begged for an opportunity to experiment with an idea he had to rouse the lifeless infant. A tub of ice was ordered and the young doctor plunged the baby into it. Out came the screaming little Parks and he was named Gordon after the doctor who prodded him to life.”
—Sir John Floyer, 1697
1861 English surgeon named Dr. William John Little (who suffered from clubfoot) described “Little’s Disease”, spastic diplegia, following complicated deliveries. He suggested that the condition was caused by a lack of oxygen during labor; which in turn caused brain damage.
Plato
Painting by Mantegna 1465
Dr. William John Little
Dr. Sigmund Freud
1950's
1958 Silverman Study
1958 Miller & Westin
James Miller and Bjorn Westin demonstrated that rapid cooling prolonged survival in "asphyxia neonatorum" refractory to conventional therapy
Westin B. Infant resuscitation and prevention of mental retardation. Am J Obstet Gynecol. 1971;110:1134–1138
Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics.1958;22:876–886
John S. Wyatt and Marianne Thoresen. Hypothermia treatment and the newborn. Pediatrics 1997;100;1028
clinical study of 10 term infants. Apgar of 1. Cooled in cold water baths until spontaneous respiration or rectal temp of 27°C. 9 survived and at f/u at 10 years, none w/ CP or neuromotor impairment. Larger study treated 65 of 4400 infants. 52 survived - no CP
182 preterm infants. Survival 68% in hypothermic (28.9°C) vs. 83% in normothermic (31.7°C air) incubators
HIE - Background
Incidence 2-5/1000 live term infants
15-25% mortality (50-75% with Severe HIE - WHO)
25 to 30% survive with significant impairment (upto 80% with Severe HIE)
Mental Retardation
Learning disabilities
Seizure disorders
Cerebral Palsy
Incidence is tenfold higher in the developing world
No change in outcomes despite advances in neonatal care
Treatment for HIE
Supportive Care:
Maintenance of adequate ventilation
Maintenance of adequate perfusion and acid-base balance
Avoid hyperthermia
Maintenance of euglycemia
Control of seizures
Control of cerebral edema
Clinical Trials
Epochs of Injury
Antepartum 20%
Intrapartum 35%
Intrapartum +/- antepartum 35%
Postnatal 10%
HIE - History
Antenatal/Intrapartum
IUGR, LGA, Infant of Diabetic Mother
Abruption, shoulder dystocia, cord prolapse
Chorioamnionitis
APGARS
Fetal Heart Rate
Nonstress test (NST)
Biophysical profile (BPP)
Scalp pH (< 7)
Meconium in amniotic fluid
Sarnat H.B, Sarnat M.S.: Neonatal encephalopathy following fetal distress. Arch Neurol. 33: 698-705. 1976
Energy Failure -- Biphasic
Primary
Partial recovery with reperfusion
Secondary (latent)
Delayed cell injury
Up to 24 hours
Despite adequate oxygenation and perfusion
Area for intervention COOLING
HIE-Imaging and Monitoring
Continuous aEEG monitoring
Formal EEG or video EEG
Head CT only if concern for intracranial bleeding
Radiation dose that would kill 50% of people within 60days is ~5 Sv.
Natural exposure in Chicago is about 1 milliSievert (1 mSv) per year.
Radiation workers are permitted up to 20 mSv per year.
30 mSv (in a neonate) for a single CT scan
average Hiroshima survivor: 200 mSv
Radiation from CT scans done in 2007 will cause 29,000 cancers and kill nearly 15,000 Americans. (Reuters February 2010)
MR Imaging and Spectroscopy - modality of choice
Brenner and Hall, Computed Tomography – An Increasing Source of Radiation Exposure, N Engl J Med 2007; 357:2277-2284
http://www.cancer.gov/cancertopics/causes/radiation/radiation-risks-pediatric-CT
Patterns of Neuronal Injury
Selective neuronal necrosis
Neurons in the deep gray nuclei
Isolated basal ganglia injury
Posterior Limb of the Internal Capsule
Neurons in the perirolandic cortex
Parasagittal cortical injury
Subcortical white matter injury (watershed)
Cool Cap Study
234 infants in 27 centers July '99 - Sep '03. ≥36 weeks with moderate-severe neonatal encephalopathy AND abnormal aEEG
Randomized to head cooling OR conventional care
Overall death or severe disability at 18 months 55% (cooled) vs. 66% (control) not significantly different (p=.10)
After adjustment for severity of aEEG, cooling benefits infants with less severe aEEG changes (p=.009)
No benefit for those with most severe aEEG changes (p=.51)
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:663-70.
NICHD Neonatal Research Network
Effect of Whole Body Hypothermia on death or severe disability
208 infants enrolled in 16 centers, Oct '99 - May '03
Findings:
Death or moderate-severe disability in 44% cooled vs. 62% control (p=.01)
Secondary outcomes:
No increase in morbidity amongst survivors
Cerebral palsy observed in 19% cooled vs. 30% control (p=.20)
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84.
Meta-analysis of Randomized Trials
Meta-analysis of these trials (including Eicher WBC trial) reported
Overall death or disability in 118 of 237 HT vs. 158 of 241 NT, giving RR of 0.76 (0.65-0.89), P = 0.001 or a 24% reduction in risk with NNT of 6
If TOBY, ICE and Neo nEuro (n = 650) does not show any positive effect, the CI would still be less than 1 and NNT would rise to 15.
A D Edwards and D V Azzopardi. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006 March; 91(2): F127–F131.
TOBY: Total body hypothermia for neonatal encephalopathy
n=325. Dec '02 - Nov '06. Randomized WBC (163) vs. intensive care (162)
Primary outcome at 18 months was a composite of death or severe neurodevelopmental disability (NDD). No significant difference found.
Severe NDD = less than 70 MDI (BSID-II) (Mean ±SD is 100±15), a score of 3 to 5 on the GMFCS, or bilateral cortical visual impairment.
In the cooled group, 42 infants died and 32 survived with severe NDD, whereas in the noncooled group, 44 infants died and 42 had severe NDD (RR for either outcome, 0.86; 95% [CI], 0.68 to 1.07; P=0.17).
However, cooling resulted in consistent improvement in secondary outcomes, including a significant increase in the rate of survival without NDD and improved outcomes among survivors.
Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, et al; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58.
Updated Meta-analysis
3 large, randomized trials (Coolcap, NICHD, TOBY) estimated a risk ratio of 0.81 (95% CI, 0.71 – 0.93, p = 0.002) for the combined rate of death and severe disability, with NNT of 9.
normal survival (defined as survival without cerebral palsy and with mental development index and psychomotor developmental index >84 and normal vision and hearing) had a risk ratio of 1.53 (95% CI, 1.22-1.93; P < .001), with NNT of 9.
Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcome at 18 months of age following moderate hypothermia in newborn infants with hypoxic ischaemic encephalopathy. BMJ 2010;340:c363.
The Infant Cooling Evaluation (ICE)
Multicenter randomized controlled trial for infants with HIE – 276 infants from 19 centers in AUS, Canada, US and NZ
whole body cooling to 33.5°C for 72 hours will be compared with maintaining their body temperature at 37°C
Major advantage that it can be started on the field by the transport team
Avoids delay when time is of essence
Trial stopped early – loss of equipoise
Neo nEuro Network
n = 129, 111 infants evaluated at 18-21 months
Trial stopped early – loss of equipoise
rates of death or severe disability were 51% in the hypothermia group and 83% in the control group (P=.001; odds ratio: 0.21 [95% CI: 0.09-0.54]; NNT: 4 [95% CI: 3-9]).
Hypothermia also had a significant protective effect in the group with severe HIE (n=77; P=.005; odds ratio: 0.17 [95% CI: 0.05-0.57]).
Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. Epub 2010 Sep 20.
Shanghai Trial
Fudan University. May '02 - Aug '05. 12 centers.
Gestational age ≥ 37weeks and birth weight ≥ 2500 g
Randomly selected head cooling (n=100) vs. control (n=94)
nasopharyngeal temperature of 34 ±0.2°C and rectal temperature of 34.5°C to 35°C for 72 hours
Neurodevelopmental outcome was assessed at 18 months of age.
combined outcome of death and severe disability was 31% and 49% (OR: 0.47; 95% CI: 0.26-0.84; P=0.01)
mortality rate was 20% and 29% (OR: 0.62; 95% CI: 0.32-1.20; P=0.16)
severe disability rate was 14% (11/80) and 28% (19/67) (OR: 0.40; 95% CI: 0.17-0.92; P=0.01)
Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, et al; China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010 Sep;157(3):367-72, 372.e1-3. Epub 2010 May 20.
Selection Criteria
Gestational age of 35 weeks or greater
Birth weight greater than or equal to 1800g
Less than 6 hours of age
No major congenital or known chromosomal
anomalies
No immediate plans to redirect care
No significant intracranial hemorrhage
Predictors of HIE (must have
1
or
2
)
1
) Cord gas or postnatal (<1 hr) with pH ≤7.0 or base deficit ≥16
2
) If moderately acidotic (pH 7.01-7.15 OR base deficit 10-15.9) OR no blood gas available but with an identified acute perinatal event (severe late or variable decels, cord prolapse, placental abruption, uterine rupture, maternal arrest or seizure)
Must fulfill additional criteria (either of the following):
APGAR ≤5 at 10 minutes
Assisted ventilation/continued resuscitation >10 minutes
Abnormal Neurological Exam
- Seizures or Encephalopathy
Things to Do for Suspected HIE
Ask for cord pH, base deficit
If cord gas not available, need ABG within 1 hr
Notify NICU attending
Turn off overhead warmer
Remove hat
Remove heart sticker and insert plastic temp probe ~6cm into anus. Secure with tape
Things NOT TO DO
DE
LAY – absolutely time sensitive treatment! If you are not sure, ask!
OVER
COOL
ING – Make sure the rectal temp probe is in place!
HYP
ERTHERMIA - An increase in core temp of 1 deg C above normal = 3.6-4 fold increase in death/disability
HYPO
CARBIA – No human oscillators!
Potential Complications
Infection – no evidence of worsening by HT.
Hemostasis – often with abnormal clotting. HT prolongs bleeding time, 3 trials demonstrated no difference in complications related to abnormal clotting between NT and HT infants.
PPHN– initially feared that HT would worsen or even induce PPHN. The 3 trials found no difference in the prevalence of PPHN between the NT and HT groups, although prevalence varied from 10% to 25% among the trials. PPHN at randomization was used as an exclusion criterion for trial entry.
Expected side-effects
Supportive Care
Bradycardia
Hypotension
Hypoglycemia
Seizures
Clotting
Electrolytes
Skin
Metabolism of medications
Death or major neurodevelopmental disability still occurs in nearly 50% of infants ≥ 36 weeks gestational age (GA) treated with cooling.
Preterm - is the safety profile too risky?
Mild, Sarnat Grade 1: In the 3 trials, were excluded for entry; however, 5% of included infants were classified as grade 1 with or without seizures and one-third of these did not develop normally. There is significant evidence supporting the association between mild grade 1 asphyxia and subsequent poorer cognitive outcome at late childhood.
Duration – based on animal data. Adult studies have shown effects of both 12 hours and 24 hours of HT after cardiac arrest.
Depth – what’s the optimal cooling temperature?
Time of initiation – TOBY demonstrated a trend (P = 0.08) toward better outcomes if cooled within 4 hours.
EEG or other diagnostic/imaging criteria
Protective Mechanisms
Reduction in cerebral energy metabolism
Preservation of brain ATP levels
Inhibition of apoptosis (reduction of caspace-3 like activity and phosphorylation of Akt)
Inhibit glutamate release
Preserve endogenous antioxidants
Reduce Nitric oxide production
Decrease free radical production
Improve protein synthesis
Preserve N-acetylaspartate
Reduce glutathione
Inhaled Xenon: NMDA antagonist
Douglas-Escobar M, Yang C, Bennett J, et al., A pilot study of novel biomarkers in neonates with hypoxic-ischemic encephalopathy. Pediatri Res. 2010 Aug 24.
Thoresen M, Hobbs CE, Wood T et al., Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxic-ischemia. J Cereb Blood Flow Metab. 2009 Apr;29(4):707-14. Epub 2009 Jan 14.
Biomarkers to assess degree of injury: 1) Phosphorylated axonal neurofilament heavy chain (pNF-H protein), 2) Ubiquitin C-terminal hydrolase 1 (UCHL1 protein)
Kelen D and Robertson N., Experimental treatments for hypoxic ischaemic encephalopahy. Early Human Development 86: (2010) p. 369-377.
Concurrent therapies: Allopurinol, melatonin, alpha-2 agonists, anticonvulsants, erythropoietin, N-acethylcysteine
Postconditioning (ischemic preconditioning demonstrated in heart, kidney and brain)
Regeneration and Repair; stem cells
TIME IS BRAIN!!!
Ask for help if you’re not sure!
http://www.babiestoday.info/newborn/baby-birth
Therapeutic Hypothermia
Rutherford M, Malamateniou C, McGuinness A., et al., Magnetic resonance imaging in hypxic-ischaemic encephalopathy. Early Human Development. Vol 86; Issue 6, June 2010, p. 351-360.
MedVac© by Contour Fabricators


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Moderate or Severe Encephalopathy (Must have at least one finding in 3 of 6 categories)
Category
Moderate HIE
Severe HIE
Level of Consciousness
Lethargic or Obtunded
Stupor or Coma
Spontaneous Activity
Decreased Activity
No activity
Posture
Distal flexion w/ complete extension, usually enhanced by stimulation
Decerebrate posturing
Tone
Hypotonic
Flaccid
Primitive Reflexes
Weak suck or incomplete moro or strong asymmetric tonic neck reflex
Absent suck or moro
Autonomic system
Miosis or bradycardia or irregular breathing pattern
Variable/Unequal/absent light reflexes or Apnea
Beware!
THE COOL HIP HIPPO
!!!
MiniMuffs - Neonatal Noise Attenuators by Natus Medical
Different Populations
1) Preterm HIE (recruiting). Vanderbilt University. Babies 32-36 weeks with HIE. Coolcap x72 hrs. f/u at 6, 12 and 24 months.
2) CoolNEC (recruiting) Great Ormond St Hospital UK. Controlled hypothermia to 33.5C for 48 hours to reduce the severity of critical illness in neonates with severe necrotizing enterocolitis.
Cooling Followup Studies
1) TOBY Children Study (enrolling). Imperial College London. Study children 6-7 years of age over 3 years, who were in TOBY. IQ >84, the presence and severity of disabilities, educational attainment and the economic impact on families and service providers.
2) CoolCap followup Study (enrolling). University of Rochester. Phone interview 7-8 years of age.
3) NICHD (published in NEJM, May 31, 2012). Death or IQ <70 in 47% cooled vs. 62% control (p=0.06). Death 28% vs. 44% (p=0.04). Death or severe disability 41% vs. 60% (p=0.03).
Combination Therapies
1) TOBYXe (not yet recruiting). Imperial College London. Randomized to treatment with hypothermia only or hypothermia and 30% xenon for 24 hours. MRS and MRI at 4-10 days.
2) CoolXenon2 (not yet recruiting). United Bristol Healthcare. Randomized to 72 hours WBC or 72h cooling +18hr 50% Xenon. aEEG and MRI <2 weeks.
3) DANCE (not yet recruiting). University of Utah. Darbepoetin alfa (Darbe), a recombinant human erythropoietin (EPO)-derived molecule, has an extended circulating half life and comparable biological activity to EPO. The proposed study is a Phase I/II dose safety and pharmacokinetic trial of early Darbe administered with hypothermia in newborn infants with moderate to severe birth asphyxia.
4) Topiramate with hypothermia (recruiting). NeoNATI - Azienda Ospedaliero, Universitaria Meyer. Topiramate has been demonstrated to posses neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models, and has been shown to be safe in asphyxiated newborns. TPM 10 mg/kg once a day will be administered with an orogastric tube as enteric-coated granules mixed with water on arrival in the NICU, when the cooling will be begun (T0), once a day for the first 3 days of life, for a total of 3 doses per patient.
Biomarkers
1) NEOCORD (recruiting). Assistance publique Hopitaux De Marseille. Study cord blood stem cells from babies with HIE vs. healthy newborns.
2) MARBLE (recruiting). University College London. (1) To establish normative ranges for thalamic 1H MRS NAA concentration and Lac/NAA in healthy newborn infants (2) To examine the accuracies of thalamic 1H MRS NAA concentration and Lac/NAA for predicting adverse neurodevelopmental outcome in HIE
Modifying Hypothermia
1) Optimizing Cooling Trial (recruiting). NICHD 19 centers. (1) cooling for 72 hours to 33.5°C (2) cooling for 120 hours to 33.5°C (3) cooling for 72 hours to 32.0°C (4) cooling for 120 hours to 32.0°C. Evaluate whether whole-body cooling (WBC) initiated at <6 hours of age and continued for 120 hours and/or a depth at 32.0°C will reduce death and disability at 18-22 months corrected age.
2) Phase Changing Material (Ongoing). UK. examine the efficacy of phase changing material in providing satisfactory therapeutic hypothermia in neonatal encephalopathy, in a mid resource setting.
3) Late Hypothermia for HIE (recruiting). NICHD 22 Centers. Evaluate whether WBC initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks with HIE will reduce the incidence of death or disability at 18-24 months of age. Will enroll 168 infants with signs of HIE and randomly assign them to either hypothermia or a non-cooled control group.
Future Directions
Rutherford M, Malamateniou C, McGuinness A., et al., Magnetic resonance imaging in hypxic-ischaemic encephalopathy. Early Human Development. Vol 86; Issue 6, June 2010, p. 351-360.
T1 weighted images showing focal regions of abnormal high signal intensity. The severity of basal ganglia and thalamic injury can be graded into mild (a) moderate (b) and severe (c). There is already atrophy of the basal ganglia and thalami with flattening of the border of the lateral lentiform nucleus in the neonate with severe lesions.
Cortical and subcortical white matter lesions T1 weighted images level of the central sulcus (a, c) and ADC map (b). At 3 days there is minimal highlighting of the cortex of the central sulcus on conventional images (a) but marked restriction of diffusion with low signal intensity on the ADC map (b). By day 14 there is overt cortical highlighting and abnormal low signal intensity in the adjacent subcortical white matter. (c) This pattern of injury is usually present in neonates with moderate and severe basal ganglia lesions.
T2
The posterior limb of the internal capsule. T1 weighted images (top row) with T2 weighted images (bottom row). (a) Normal appearances of the posterior limb of the internal capsule (PLIC) (arrows). (b, c, d) Abnormal appearances of paired T1 and T2 weighted sequences in three different infants with HIE. It is important to use both T1 and T2 weighted sequences to assess the PLIC.
T1
T2
DWI
Day 2
Day 15
Top row: There is loss of anatomical detail throughout the brain on the T1 weighted image but the changes are quite subtle. There is some white matter high signal intensity on the T2 weighted image. The DWI shows linear areas of increased signal intensity mainly in the cortex but no larger focal lesions of altered signal intensity. However on an apparent diffusion coefficient (ADC) map all regions of the brain showed marked reduction in ADC. Values are shown with normal average value in brackets. Bottom row. At 15 days there has been widespread infarction throughout the hemispheres with abnormal signal intensity and some atrophy of the BGT seen on both T1 (left) and T2 weighted (right) images.
MR spectroscopy can detect metabolites such as lactate, N-acetyl aspartate, choline, and creatine that provide functional data regarding metabolic integrity in specific regions of the brain.
When the brain becomes ischemic, it switches to anaerobic glycolysis and lactate accumulates. Markedly elevated lactate is the key spectroscopic feature of cerebral hypoxia and ischemia. Choline is elevated, and NAA and creatine are reduced. If cerebral infarction ensues, lipids increase.
NICHD Neonatal Research Network. Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg.

Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy. Pappas A, Shankaran S, Laptook AR, Langer JC, Bara R, Ehrenkranz RA, Goldberg RN, Das A, Higgins RD, Tyson JE, Walsh MC; J Pediatr. 2010 Dec 9.
Term baby with nuchal cord, moderate encephalopathy. Cord pH of 6.96. Seizures on EEG, tx’ed with Phenobarb
(1) IPostC is effective in improving brain metabolism, normalizing cerebral blood flow and providing long term protection if initiated as late as 3 and 6 h after the index ischemia in stroke models (delayed IPostC)

Ren C, Gao X, Niu G, Yan Z, Chen X, Zhao H. Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS ONE 2008;3:e3851.

(2) remote IPostC (whereby a conditioning stimulus is induced in a remote non-vital organ such as a limb) reduces infarct size if performed immediately at reperfusion and at 3 h after reperfusion

Ren C, Gao X, Steinberg G, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience 2008;151:1099–103.
Thoresen, Hypothermia after Perinatal Asphyxia: Selection for Treatment and Cooling Protocol.
J Pediatr 2011;158:e45-9
Jacobs SE, Stewart M, Inder T,Doyle LW,Morley CJ. ICE: the Australian cooling trial for hypoxic-ischemic encephalopathy in hospital outcomes. Proceedings of theHot Topics in Neonatology Conference, Washington, DC, Dec 7-9 2008.
The basal ganglia/thalamus pattern was associated with more severe neonatal signs, including more intensive resuscitation at birth (P = .001), more severe encephalopathy (P = .0001), and more severe seizures (P = .0001).

The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months.

Miller et al., Patterns of brain injury in term neonatal encephalopathy. (J Pediatr 2005;146:453-60)
Cerebral palsy was associated with God's wrath, witchcraft, the evil eye, or maternal imagination. In the Middle Ages, the midwife's negligence or difficult teething was held responsible.
‘‘The devil replaces legitimate children with changelings and killcrops to plague mankind. He often pulls certain girls into the water, impregnates them, and keeps them with him until they deliver their children; he then places those children in cradles, taking the legitimate children away.’’ Martin Luther’s proposal to drown these infants was later resumed by Werner Catel, a Leipzig pediatrician who helped organize the murder of handicapped children in Nazi Germany.
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