Mild Hypothermia and the Distribution of Cerebral Lesions in Neonates With Hypoxic-Ischemic Encephalopathy
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《小儿科》
Imaging Sciences Department, Robert Steiner Magnetic Resonance Unit
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
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
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 2 test with Fisher's exact test where appropriate.
RESULTS
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.
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).
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).
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).
DISCUSSION
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.
No conflict of interest declared.
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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
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
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 2 test with Fisher's exact test where appropriate.
RESULTS
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.
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).
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).
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).
DISCUSSION
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.
No conflict of interest declared.
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