Published online September 30, 2005
PEDIATRICS Vol. 116 No. 4 October 2005, pp. 1001-1006 (doi:10.1542/peds.2005-0328)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (20)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rutherford, M. A.
Right arrow Articles by Thoresen, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rutherford, M. A.
Right arrow Articles by Thoresen, M.
Related Collections
Right arrow Premature & Newborn

SPECIAL ARTICLE

Mild Hypothermia and the Distribution of Cerebral Lesions in Neonates With Hypoxic-Ischemic Encephalopathy

Mary A. Rutherford, FRCR, FRCPCH*, Denis Azzopardi, MD, FRCPCH{ddagger}, Andrew Whitelaw, MD, FRCPCH§, Frances Cowan, PhD, MRCPCH{ddagger}, S. Renowden, FRCR||, A. David Edwards, FMedSci*,{ddagger} and Marianne Thoresen, MD, PhD§,||

* Imaging Sciences Department, Robert Steiner Magnetic Resonance Unit
{ddagger} Department of Paediatrics, Imperial College, Hammersmith Hospital, London, United Kingdom
§ Department of Clinical Sciences, Child Health, Southmead and St Michael's Hospital, University of Bristol, Bristol, United Kingdom
|| Department of Neuroradiology, Frenchay Hospital, Bristol, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hypothermia induced by whole-body cooling (WBC) and selective head cooling (SHC) both reduce brain injury after hypoxia-ischemia in newborn animals, but it is not known how these treatments affect the incidence or pattern of brain injury in human newborns. To assess this, 14 term infants with hypoxic-ischemic encephalopathy (HIE) treated with SHC, 20 infants with HIE treated with WBC, and 52 noncooled infants with HIE of similar severity were studied with magnetic resonance imaging in the neonatal period. Infants fulfilling strict criteria for HIE were recruited into the study after assessment of an amplitude-integrated electroencephalography (aEEG). Cooling was commenced within 6 hours of birth and continued for 48 to 72 hours. Hypothermia was not associated with unexpected or unusual lesions, and the prevalence of intracranial hemorrhage was similar in all 3 groups. Both modes of hypothermia were associated with a decrease in basal ganglia and thalamic lesions, which are predictive of abnormal outcome. This decrease was significant in infants with a moderate aEEG finding but not in those with a severe aEEG finding. A decrease in the incidence of severe cortical lesions was seen in the infants treated with SHC.

Key Words: brain imaging • hypothermia • hypoxic-ischemic encephalopathy • neonates

Abbreviations: HIE, hypoxic-ischemic encephalopathy • WBC, whole-body cooling • SHC, selective head cooling • aEEG, amplitude-integrated electroencephalography • BGT, basal ganglia and thalamus • PLIC, posterior limb of the internal capsule • WM, white matter

Perinatal hypoxic-ischemic brain injury remains an important cause of neurologic disability accounting for 15% to 28% of children with cerebral palsy.1 The current treatment for infants with hypoxic-ischemic encephalopathy (HIE) is supportive, with prompt treatment of convulsions and stabilization of physiologic parameters. Animal studies have shown that mild hypothermia with a reduction in body temperature by 3 to 4°C immediately after hypoxic-ischemia preserves cerebral energy metabolism, reduces cytotoxic edema, and improves histologic and functional outcome.2–16 Two methods of achieving hypothermia have been used. The majority of animal studies and clinical trials have used whole-body cooling (WBC), but selective head cooling (SHC) has also been used in an attempt to minimize the risk of systemic (cardiorespiratory) adverse effects.17 With WBC, a mattress or similar device is used to cool the trunk, limbs, and head, which reduces body temperature to 33 to 34°C with minimal gradient between the trunk and brain. In contrast, SHC has used a cap through which cold water flows and warming is applied to the trunk to prevent rectal temperature falling below 34°C.

The effects of hypothermia may be influenced by the time of initiation of cooling after injury and the duration of cooling. Animal studies have shown that cooling starting 6 hours after a hypoxic-ischemic event had no beneficial effect.7 Studies have also shown no effect if cooling is discontinued too early,13 and most trials now recommend a cooling period of 48 to 72 hours. Pilot studies using early cooling in term infants have shown no deleterious effects from mild hypothermia under intensive-care conditions, although there has been a suggestion of an increase in the incidence of intracranial hemorrhage.17–24 Data from controlled trials are now beginning to suggest that both SHC and WBC may lead to improved outcomes.23–27

HIE in neonates can be graded as mild, moderate, and severe on clinical grounds.28 However, these clinical signs may take ≥24 hours to develop maximally, and therefore an earlier measurement of severity is required to recruit suitable infants into cooling trials. Amplitude-integrated electroencephalography (aEEG) within the first 24 hours after birth is predictive of outcome and is being used by some clinical trials as an additional selection criterion for hypothermia treatment.23,29 Recruitment requires an abnormal aEEG trace with the presence of seizures or abnormalities in background activity. aEEG traces can be classified as having moderately abnormal amplitude (grade II), with the lower margin of the trace <5 µV, or severely depressed amplitude (grade III), with the upper margin of the trace <10 µV. In addition, aEEG is classified according to the presence or absence of seizures.29 This approach ensures that a high proportion of enrolled infants have significant encephalopathy and a high chance of adverse outcome.

Magnetic resonance imaging (MRI) provides excellent detail of the brain lesions characteristic of perinatal hypoxic-ischemic injury: these lesions can be graded, and the pattern of involvement can be related to outcome. In particular, lesions in the basal ganglia and thalamus (BGT) and posterior limb of the internal capsule (PLIC) are predictive of cerebral palsy30–32 in infants with HIE. Less commonly, infants with HIE sustain mainly white matter (WM) lesions, which are associated with later cognitive impairments; the more extensive the WM abnormalities, the more marked the impairment.33 The effect of hypothermia on the pattern of these brain lesions in neonates with HIE is not known.

The primary aim of this study was to ascertain whether hypothermia alters the patterns of injury usually identified in infants with HIE. Two secondary aims were to explore whether (1) the imaging findings relate to the aEEG data and (2) the method of cooling influences lesion distribution.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Entry criteria were (1) gestational age of ≥36 weeks (excluding those with metabolic or congenital abnormalities); (2) need for resuscitation and an Apgar score of <5 at 5 minutes on cord, first arterial blood pH < 7.1, or base deficit >16 mmol/L; (3) presence of encephalopathy with at least 1 of the following: hypotonia, abnormal reflexes, absent or weak suck, or clinical seizures; and (4) an aEEG with either moderate II or severe III abnormality, or seizures, performed within 24 hours of delivery.29 Permission for the study of hypothermic therapy was given by the relevant ethical review boards, and infants were treated and imaged after parental consent.

Cooling
The cooled infants were in 2 groups: WBC and SHC. WBC to a rectal temperature of 33 to 34°C for 48 to 72 hours was achieved by using a Polar Air blanket (Augustine Medical, Eden Prairie, MD), a Tecotherm cooling mattress (TecCom GmbH, Munich, Germany), or placing latex gloves filled with cold water around the body. SHC with mild systemic hypothermia to a rectal temperature of 34.5°C for 72 hours was achieved with the Cool Care system (Olympic Medical, Seattle, WA), which has a cap that is around the head and circulates cold water.

Twenty-six of the infants were in 2 randomized trials: the Cool Cap Trial and the Total Body Hypothermia (TOBY) Trial. The scientific advisory committees of both trials approved this secondary study. The remaining cooled infants were enrolled onto pilot studies conducted before these 2 trials were recruiting.

All infants were monitored and treated in a standard manner with attention to maintenance of normal blood gases, blood pressure, fluid balance and renal function, hypoglycemia, jaundice, bleeding tendencies, and seizure management. Temperature control in infants who were not cooled and not part of the Cool Cap or TOBY trials was according to standard clinical practice, which was to keep the axillary temperature at 37 ± 0.2°C.

Image Acquisition
Images were acquired at 1 or 1.5 T on a Philips Eclipse or General Electric system with T1- and T2-weighted spin-echo sequences in the transverse and sagittal planes.

Image Analysis
Images were assessed for normal anatomic development and for the presence of abnormal signal intensities within the BGT, WM, and cortex by experienced neuroradiologists (M.A.R. and S.R.) who were blind to treatment. All lesions were classified as mild, moderate, or severe as previously published.30 The presence of moderate or severe BGT with or without cortical lesions or severe WM lesions, known to be associated with abnormal outcome, was specifically sought (Fig 1). Data for the groups were compared by using the {chi}2 test with Fisher's exact test where appropriate.


Figure 1
View larger version (49K):
[in this window]
[in a new window]
  		Fig 1. (A) T1-weighted image: normal appearances for a term born neonate. There is high signal intensity from myelin in the PLIC (arrow). (B) Severe basal ganglia lesions with abnormal high signal intensity within the thalami and lentiform nuclei (arrows). The intervening PLIC has an abnormally low signal intensity. (C) T1-weighted image: bilateral basal ganglia lesions and multiple areas of WM infarction (arrows).

 

   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Eighty-six term newborns with HIE and moderately (grade II) or severely (grade III) abnormal aEEG findings were imaged, 34 infants were cooled, and 56 received standard care without cooling.

Birthweight and gestational age were similar in the cooled versus the noncooled groups. The proportion of moderate to severe aEEG findings was similar between the groups and was moderate in 14 (41.2%) of the 34 cooled infants and in 18 (34.6%) of 52 noncooled infants. In the noncooled infants with aEEG performed within the first 6 hours, there were 10 (48%) of 21 infants with a moderate aEEG finding. Of the 34 cooled infants, 14 underwent SHC and 20 had WBC.

The head-cooled group underwent MRI, on average, 2 days later than the other groups, but all examinations were made at a time when MRI can identify the pattern of a perinatal injury and provide reliable predictive data. Clinical details for all 3 groups are shown in Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical and Imaging Details of All the Infants

 
Pattern of Lesions
The most frequently observed lesions were those involving the BGT (Table 2). BGT lesions, of all grades, were seen in 46 (88.4%) of 52 noncooled infants, 7 (50%) of 14 infants with SHC, and 15 (75%) of the 20 infants with WBC. Moderate and severe BGT lesions that are known to be associated with later impairments were found in 43 (82.6%) of 52 noncooled infants, 4 (28.6%) of 14 infants with SHC, and 7 (35%) of 20 infants with WBC. This was a highly significant reduction with the presence of cooling (P < .0001). Minimal BGT lesions were observed more commonly in the cooled infants than the noncooled infants: 5.8% of noncooled infants, 21.4% of SHC infants, and 30% of WBC infants (P = .01).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Lesions Seen on MRI

 
BGT lesions were often accompanied by abnormalities in the WM and cortex (Fig 1). Severe WM lesions were seen in 18 (34.6%) noncooled infants, in 2 (14.3%) infants with SHC, and in 5 (25%) infants with WBC (P = .30). Of the 18 infants with severe WM lesions, 17 also had some degree of BGT involvement.

Cortical lesions were detected equally in noncooled (42 of 52 [81%]) and cooled (21 of 34 [62%]) infants. However, cooled infants had fewer major cortical lesions: moderate or severe cortical lesions were seen in 33 (63.5%) of 52 in the noncooled group, 5 (35.7%) of 14 in the SHC group, and 8 (40%) of 20 in the WBC group (P = .025). To examine further whether there was any preferential protection of the cortex with cooling, the proportion of isolated BGT lesions with no cortical abnormalities was determined. Isolated BGT lesions were seen in 12 (23%) of 52 noncooled infants and 5 (14.7%) of 34 of cooled infants. This difference was not significant. Severe cortical lesions, however, were seen in none of the infants with SHC but were seen in 5 (25%) of 20 of those with TBC and in 14 (27%) of 52 noncooled infants (P = .01).

There were no unusual patterns of injury in the neonates treated with hypothermia, and the prevalence of hemorrhage was similar (between 30% and 40%) in all 3 groups (P = .69) (Table 2). The majority of hemorrhagic lesions were small subdural hemorrhages, which should not influence outcome. However, 1 infant in the WBC group had a large parenchymal hemorrhage with midline shift (Fig 2); this infant died. Another infant, with a severe coagulopathy before trial entry, developed a large hemispheric subdural hemorrhage with midline shift during head cooling, which resolved spontaneously (Fig 3).


Figure 2
View larger version (104K):
[in this window]
[in a new window]
  		Fig 2. Infant who received WBC and showed a large hemorrhagic lesion, seen as low signal intensity within the left parietal and temporal lobes. This was associated with displacement and compression of the BGT and considerable midline shift. The remaining WM has an abnormally high signal intensity consistent with edema or ischemia. The ventricular system is dilated. This infant died within the first week of life.

 

Figure 3
View larger version (100K):
[in this window]
[in a new window]
  		Fig 3. Infant receiving SHC with extensive subdural hemorrhage seen as high signal intensity on these T1-weighted images. There is an additional cephalhematoma (arrowhead). This infant survived, and the hemorrhage resolved spontaneously.

 
Frequency of Lesions and aEEG Findings
There were significantly fewer BGT lesions known to be associated with an abnormal outcome in the cooled infants. This significance was maintained when only those noncooled infants (n = 21) with an early (< 6 hours after birth) aEEG were included (P = .001). The effect of cooling, however, was seen only in those infants with a moderate (grade II) aEEG finding. The proportion of moderate or severe BGT lesions in moderate (grade II) aEEG findings was 77.8% in the noncooled infants compared with 12.5% and 0% in the SHC and WBC infants, respectively (P < .0001). The significance was maintained when only noncooled infants with an early (<6 hours after birth) aEEG were included (Table 3). The proportion of moderate or severe BGT lesions in severe (grade III) aEEG findings was 88.2% compared with 66.7% and 71.4% in the SHC and WBC infants, respectively (P = .06).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Infants With Prognostically Significant Lesions: Moderate or Severe BGT Lesions According to aEEG Severity

 

   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this preliminary study, treatment with mild hypothermia in neonates with moderate HIE was associated with a reduction in lesions within the BGT, which are known to be associated with an abnormal neurodevelopmental outcome. The effects of cooling were seen with both methods of producing mild hypothermia. Protection was seen largely in infants with moderate aEEG abnormalities, suggesting that only infants with a less severe insult may respond to neuroprotective intervention The recent Cool Cap Trial showed significant improvement in survival without severe disabilities only in infants without the most severe aEEG abnormalities.23 In addition to a decrease in BGT lesions in the cooled infants, the distribution of severity was different, with relatively more mild BGT lesions observed in the cooled groups, which suggests modification of potentially more severe lesions. Mild BGT lesions may be associated with minor motor impairments, and follow-up studies correlating imaging and outcome in these infants are clearly needed.

Although this was an observational study, the enrollment criteria were similar for both cooled and noncooled infants, and the same method of assessment of the aEEG was used. We used a locally developed classification system for grading aEEG results, which may differ slightly from those used in other centers, but the system has been validated.34,35 Although the proportions of infants with moderate or severe aEEG abnormalities were similar between cooled and noncooled infants, the aEEG was recorded later in the noncooled infants. Because the aEEG may improve over the first few hours after asphyxia,34–36 an accurate comparison of the aEEG between cooled and noncooled infants is not possible. However, when we compared only those infants with an aEEG recording within 6 hours of birth, the decrease in BGT lesions in cooled infants remained significant.

The patterns of brain injury documented in infants who underwent cooling were similar to those seen and previously reported after HIE. Hypothermia down to 33°C is known to reduce platelet function, and temperatures <33°C are known to reduce clotting enzymes37; therefore, it is pertinent that cooling in this study was not associated with an increase in hemorrhagic lesions. Although the 2 infants with extensive hemorrhage were in the cooled group, subdural hemorrhage is relatively common in infants with HIE, and hemorrhagic lesions within the parenchyma have also been described38

This study enrolled infants who underwent 2 different methods for cooling: WBC or SHC. A study in neonatal swine compared head cooling with body cooling and found a significant temperature gradient across the brain with head cooling,39 although this gradient was reduced in the presence of hypoxia. In a piglet model of head cooling, the cortex was cooled to 26°C and the deep brain to 30°C, and these gradients were maintained for the full 24-hour cooling period.16 In that study there were equal degrees of neuroprotection in both cortex and BGT.3 However, the different size and geometry of the piglet head means that caution is needed when extrapolating these results, as suggested by the results of computer modeling, which do not predict cross-brain gradients in newborn infants.40

Cortical abnormality frequently accompanies the classic lesions seen in the BGT after acute hypoxia-ischemia. These cortical abnormalities are seen most frequently along the central sulcus and along the medial aspect of the interhemispheric fissure.31 Cortical areas are often thought to be susceptible to hypoxia-ischemia because of a relatively high metabolic rate in the tissue around the central sulcus related to maturation and early myelination. The cortical abnormalities seen on MRI are thought to represent laminar necrosis in the deep layers of the cortex. We did not show a significant difference in cortical abnormalities in infants that had been cooled or not cooled. However, although the numbers are small, the infants who were treated with SHC had a lower proportion of severe cortical lesions than the infants cooled with WBC and the noncooled group. Differential protection of the cortex was suggested in a recent study in which systemic hypothermia of 33 to 34°C was induced with body cooling alone; fewer cortical lesions were demonstrated on later MRI in the cooled infants.24 However, the numbers in this study were relatively small, infants were recruited from 35 weeks' gestation (mean gestational age: 38.7 weeks), and infants were not recruited on the basis of aEEG findings; therefore this measure of insult severity could not be considered in the analysis. Cortical lesions are not usually sustained in infants with signs of acute HIE born at <38 weeks' gestation.41 In addition, cortical lesions may not be apparent soon after injury and therefore may be missed on early imaging.32 The decrease in cortical lesions in that study could therefore be because of the recruitment of more immature infants or of less severely injured infants who are likely to have isolated mild or moderate BGT lesions.

Approximately 40% of infants with significant BGT lesions after HIE will have additional WM infarction. Because some infants with HIE show only WM abnormalities without BGT involvement, it is likely that the 2 patterns reflect slightly different pathogenesis.33 Animal models have shown that priming with infection lowers the threshold for infarction after a hypoxic-ischemic insult. Infants with bacterial or viral CNS infection usually demonstrate WM abnormalities on MRI. In animal fetal asphyxia models, increased WM involvement has been demonstrated when infection is combined with hypoxia-ischemia.42–44 We were unable to show a decrease in severe WM abnormalities in hypothermic infants in this study, although the numbers involved were small, which may reflect a role for infection or a more chronic insult that is less sensitive to cooling. Although in a fetal sheep model early cooling protected against WM injury, in contrast to the asphyxiated human neonate, the pattern of injury usually sustained in this animal model is predominantly WM rather than BGT.7

Clearly, it is essential to understand the spectrum of lesions that may be sustained by infants with perinatal brain injury to develop strategies for intervening after perinatal asphyxia. There are several ongoing hypothermia trials in infants with HIE, but the clinical outcome of these trials may not be available for several years. Intensive early brain imaging in association with these trials will allow us to directly examine the effect of hypothermia on brain-lesion acquisition. Brain MRI uniquely enables assessment of the distribution and frequency of brain lesions and should be included in future studies of neuroprotective interventions.


   ACKNOWLEDGMENTS
 
We would like to thank the following organizations for financial support: the Medical Research Council; the Academy of Medical Sciences; the Health Foundation; SPARKS (Sport Aiding Medical Research for Kids); The Wellcome Trust; and the Norwegian Research Council. We would also like to thank the Cool Cap Trial and the TOBY (Total Body Hypothermia) Trial at www.npeu.ox.ac.uk/Toby for permission to perform and publish this study.


   FOOTNOTES
 
Accepted Jul 1, 2005.

Reprint requests to (M.A.R.) Imaging Sciences Department, Robert Steiner MR Unit, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom. E-mail: m.rutherford{at}imperial.ac.uk

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991–94. Acta Paediatr. 2001;90 :271 –277[ISI][Medline]
  2. Thoresen M. Cooling the newborn after asphyxia—physiological and experimental background and its clinical use. Semin Neonatol. 2000;5 :61 –73[CrossRef][Medline]
  3. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol. 2003;53 :65 –72[CrossRef][ISI][Medline]
  4. Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, et al. Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats. Brain Res. 2004;1019 :217 –225[CrossRef][ISI][Medline]
  5. Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in mammalian central nervous system. J Cereb Blood Flow Metab. 2003;23 :513 –530[CrossRef][ISI][Medline]
  6. Leonov Y, Sterz F, Safar P, Radovsky A. Moderate hypothermia after cardiac arrest of 17 minutes in dogs. Effect on cerebral and cardiac outcome. Stroke. 1990;21 :1600 –1606[Abstract/Free Full Text]
  7. Roelfsema V, Bennet L, George S, et al. Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. J Cereb Blood Flow Metab. 2004;24 :877 –886[Medline]
  8. Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun. 1995;217 :1193 –1199[CrossRef][ISI][Medline]
  9. Agnew DM, Koehler RC, Guerguerian AM, et al. Hypothermia for 24 hours after asphyxic cardiac arrest in piglets provides striatal neuroprotection that is sustained 10 days after rewarming. Pediatr Res. 2003;54 :253 –262[CrossRef][ISI][Medline]
  10. Zhu C, Wang X, Cheng X, et al. Post-ischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia. Brain Res. 2004;996 :67 –75[CrossRef][Medline]
  11. Hickey RW, Ferimer H, Alexander HL, et al. Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med. 2000;28 :3511 –3516[CrossRef][Medline]
  12. Van de Berg WD, Schmitz C, Steinbusch HW, Blanco CE. Perinatal asphyxia induced neuronal loss by apoptosis in the neonatal rat striatum: a combined TUNEL and stereological study. Exp Neurol. 2002;174 :29 –36[CrossRef][Medline]
  13. Laptook AR, Corbett RJ, Burns DK, Sterett R. A limited interval of delayed modest hypothermia for ischemic brain resuscitation is not beneficial in neonatal swine. Pediatr Res. 1999;46 :383 –389[Medline]
  14. Laptook AR, Corbett RJ. The effects of temperature on hypoxic-ischemic brain injury. Clin Perinatol. 2002;29 :623 –649[CrossRef][ISI][Medline]
  15. Coimbra C, Wieloch T. Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol (Berl). 1994;87 :325 –331[Medline]
  16. Thoresen M, Simmonds M, Satas S, Tooley J, Silver IA. Effective selective head cooling during posthypoxic hypothermia in newborn piglets. Pediatr Res. 2001;49 :594 –599[ISI][Medline]
  17. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics. 2000;106 :92 –99[Abstract/Free Full Text]
  18. Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. Pediatrics. 2003;111 :244 –251[Abstract/Free Full Text]
  19. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics. 2001;107 :480 –484[Abstract/Free Full Text]
  20. Lista G, Pogliani L, Fontana P, Castoldi F, Compagnoni G. Cardiovascular and respiratory status in mechanically ventilated asphyxiated term infants: comparison between hypothermic and control group. Acta Biomed Ateneo Parmense. 2004;75 :107 –113[Medline]
  21. Shankaran S, Laptook A, Wright LL, et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002;110 :377 –385[Abstract/Free Full Text]
  22. Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics. 2000;106 :684 –694[Abstract/Free Full Text]
  23. Gluckman P, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005:365 :663 –670.[ISI][Medline]
  24. Inder TE, Hunt RW, Morley CJ, et al. Randomized trial of systemic hypothermia selectively protects the cortex on MRI in term hypoxic-ischemic encephalopathy. J Pediatr. 2004;145 :835 –837[CrossRef][ISI][Medline]
  25. Shankaran S. The NICHD Trial on Body Cooling. Presented at: Hot Topics in Neonatology; December 14–15, 2004; Washington, DC
  26. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32 :11 –17[CrossRef][ISI][Medline]
  27. Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr Opin Neurol. 2005;18 :111 –116[ISI][Medline]
  28. Levene MI, Sands C, Grindulis H, Moore JR. Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet. 1986;1 (8472):67–69
  29. al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics. 1999;103 :1263 –1271[Abstract/Free Full Text]
  30. Mercuri E, Rutherford M, Barnett A, et al. MRI lesions and infants with neonatal encephalopathy. Is the Apgar score predictive? Neuropediatrics. 2002;33 :150 –156[CrossRef][ISI][Medline]
  31. Rutherford M, Pennock J, Schwieso J, Cowan F, Dubowitz L. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed. 1996;75 :F145 –F151
  32. Rutherford MA, Pennock JM, Counsell SJ, et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics. 1998;102 :323 –328[Abstract/Free Full Text]
  33. Cowan F, Dubowitz L, Mercuri E, Counsell S, Rutherford M. White matter injury can lead to cognitive impairment without major motor deficits following perinatal asphyxia and early encephalopathy. Dev Med Child Neurol Suppl. 2003;93 :45:14
  34. Toet MC, Hellstrom-Westas L, Groenendaal F, Eken P, de Vries LS. Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 1999;81 :F19 –F23[Abstract/Free Full Text]
  35. Shalak LF, Laptook AR, Velaphi SC, Perlman JM. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics. 2003;111 :351 –357[Abstract/Free Full Text]
  36. ter Horst HJ, Sommer C, Bergman KA, Fock JM, van Weerden TW, Bos AF. Prognostic significance of amplitude-integrated EEG during the first 72 hours after birth in severely asphyxiated neonates. Pediatr Res. 2004;55 :1026 –1033[CrossRef][ISI][Medline]
  37. Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56 :1221 –1228[ISI][Medline]
  38. Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet. 2003;361 :713 –714[CrossRef][ISI][Medline]
  39. Laptook AR, Shalak L, Corbett RJ. Differences in brain temperature and cerebral blood flow during selective head versus whole-body cooling. Pediatrics. 2001;108 :1103 –1110[Abstract/Free Full Text]
  40. Van Leeuwen GM, Hand JW, Lagendijk JJ, Azzopardi DV, Edwards AD. Numerical modeling of temperature distributions within the neonatal head. Pediatr Res. 2000;48 :351 –356[ISI][Medline]
  41. Barkovich AJ, Sargent SK. Profound asphyxia in the premature infant: imaging findings. AJNR Am J Neuroradiol. 1995;16 :1837 –1846[Abstract]
  42. Jensen A, Garnier Y, Middelanis J, Berger R. Perinatal brain damage—from pathophysiology to prevention. Eur J Obstet Gynecol Reprod Biol. 2003;110 :S70 –S79
  43. Mallard C, Welin AK, Peebles D, Hagberg H, Kjellmer I. White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res. 2003;28 :215 –223[CrossRef][ISI][Medline]
  44. Berger R, Garnier Y, Jensen A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002;9 :319 –328[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 StrokeHome page
M. Yenari, K. Kitagawa, P. Lyden, and M. Perez-Pinzon
Metabolic Downregulation: A Key to Successful Neuroprotection?
Stroke, October 1, 2008; 39(10): 2910 - 2917.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Neuroradiol.Home page
J.M. Pollock, C.T. Whitlow, A.R. Deibler, H. Tan, J.H. Burdette, R.A. Kraft, and J.A. Maldjian
Anoxic Injury-Associated Cerebral Hyperperfusion Identified with Arterial Spin-Labeled MR Imaging
AJNR Am. J. Neuroradiol., August 1, 2008; 29(7): 1302 - 1307.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
J. S. Wyatt, P. D. Gluckman, P. Y. Liu, D. Azzopardi, R. Ballard, A. D. Edwards, D. M. Ferriero, R. A. Polin, C. M. Robertson, M. Thoresen, et al.
Determinants of Outcomes After Head Cooling for Neonatal Encephalopathy
Pediatrics, May 1, 2007; 119(5): 912 - 921.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
E. De Vita, A. Bainbridge, J. L. Y. Cheong, C. Hagmann, R. Lombard, W. K. Chong, J. S. Wyatt, E. B. Cady, R. J. Ordidge, and N. J. Robertson
Magnetic Resonance Imaging of Neonatal Encephalopathy at 4.7 Tesla: Initial Experiences
Pediatrics, December 1, 2006; 118(6): e1812 - e1821.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
M. Thoresen, A. Whitelaw, D. Azzopardi, S. Renowden, A. D. Edwards, and M. A. Rutherford
Does Oxygen Concentration Used for Resuscitation Influence Outcome of Asphyxiated Newly Born Infants Treated With Hypothermia?: In Reply
Pediatrics, June 1, 2006; 117(6): 2328 - 2328.
[Full Text] [PDF]

Home page
 PediatricsHome page
M. Vento, R. Escrig, P. Saenz, I. Izquierdo, J. Sastre, and J. Vina
Does oxygen concentration used for resuscitation influence outcome of asphyxiated newly born infants treated with hypothermia?
Pediatrics, June 1, 2006; 117(6): 2326 - 2328.
[Full Text] [PDF]

Home page
 NEJMHome page
K. H. Polderman, A. R.J. Girbes, K. B. Nelson, A. Leviton, P. D. Gluckman, A. J. Gunn, J. S. Wyatt, S. Shankaran, A. R. Laptook, and the National Institute of Child Health and Human D
Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy
N. Engl. J. Med., April 13, 2006; 354(15): 1643 - 1645.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (20)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rutherford, M. A.
Right arrow Articles by Thoresen, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rutherford, M. A.
Right arrow Articles by Thoresen, M.
Related Collections
Right arrow Premature & Newborn