Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?)

Gagné-Loranger, Maude; Sheppard, Megan; Ali, Nabeel; Saint‐Martin, Christine; Wintermark, Pia

doi:10.1055/s-0035-1563712

Cited by 64 publications

(47 citation statements)

References 27 publications

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“…7 Additionally in a recent cohort study, Gange-Loranger et al reported that among 13 infants with mild NE who underwent TH, 31% (4/13) had MRI changes consistent with HI injury. 26 The rate of both any MRI abnormality, and MRI hypoxic-ischemic injury, among those with mild NE in these studies is consistent with our own findings. However none of these studies provided sufficient details regarding the pattern or severity of MRI cerebral injuries to allow further meaningful comparison across studies.…”

Section: Discussionsupporting

confidence: 91%

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy

Walsh

Neil

Morey

et al. 2017

The Journal of Pediatrics

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Objective To assess and contrast the incidence and severity of abnormalities on cerebral magnetic resonance imaging (MRI) between infants with mild, moderate, and severe neonatal encephalopathy who received therapeutic hypothermia. Study design This is a retrospective cohort study of infants with mild, moderate, and severe NE who received TH at a single tertiary neonatal intensive care unit (NICU) between 2013 and 2015. Two neuro-radiologists masked to the clinical condition evaluated brain MRIs for cerebral injury following TH using the Barkovich classification system. Additional abnormalities not included in this classification system were also noted. The rate, pattern, and severity of abnormalities/injury were compared across the grades of NE. Results Eighty-nine infants received TH and met study criteria – 48 with mild NE, 35 with moderate NE, and six with severe NE. Forty-eight infants (54%) had an abnormality on MRI. There was no difference in the rate of overall MRI abnormalities by grade of NE (mild NE 54%, moderate NE 54%, and severe NE 50%, p=0.89). Basal ganglia/thalamic injury was more common in those with severe NE (mild NE 4%; moderate NE 9%; severe NE 34%, p=0.03). In contrast, watershed injury did not differ between NE grades (mild NE 36%; moderate NE 32%; severe NE 50%, p=0.3) Conclusion Mild NE is commonly associated with MRI abnormalities after TH. The grade of NE during the first hours of life may not adequately discriminate between infants with and without cerebral injury noted by MRI after TH.

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Section: Discussionsupporting

confidence: 91%

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy

Walsh

Neil

Morey

et al. 2017

The Journal of Pediatrics

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“…Limitations of PRIME are the long period required for enrollment, absence of follow-up aEEG at different time points or continuously, absence of all outcome measures on some infants, and the relative center imbalance in patient enrollment (Supplemental material -Appendix). During study design there were limited data on short-term outcomes of mild NE infants 6,7 and systematic data on long-term outcomes (from the pre-hypothermia era) was favorable 4,5 . Thus, a low frequency of short-term abnormalities was expected and our primary objective was to determine if mild NE diagnosed at < 6h of age was associated with short-term neurological abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…2 Infants in whom the worst level of encephalopathy during hospitalization was mild had few if any adverse outcomes. [2][3][4][5] Recently, studies have suggested that some infants with perinatal acidosis and mild NE diagnosed at < 6h of age have neurological abnormalities at discharge from the neonatal intensive care unit (NICU) 6 , cerebral findings of hypoxic-ischemic injury on brain magnetic resonance imaging (MRI) 7 , or high rates of disability at 5 years of age. 8 However, a prospective and systematic evaluation of the frequency of neurological abnormalities of these mild NE infants is lacking.…”

Section: Introductionmentioning

confidence: 99%

Prospective research on infants with mild encephalopathy: the PRIME study

et al. 2017

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“…A moderate degree of injury (30-60% tissue loss) is required to see a neuroprotective effect of HT in this model [31,53] . Whether mild injury should be eligible for cooling in neonates is still debated, as the neuroprotective effect of HT has not been clarified for these patients [54] . Rat pups are highly variable in how much hypoxia they can withstand before cellular death is seen, and the same is likely to be the case for human neonates.…”

Section: Discussionmentioning

confidence: 99%

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

et al. 2017

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Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, early-onset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. Seven-day-old Wistar rats (n = 178) were subjected to intraperitoneal injections of PAM₃CSK₄ (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-h delay, the left carotid artery was ligated followed by 50 min of hypoxia (8% O₂) at a rectal temperature of 36°C. Pups received a 5-h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the insult. Brains were harvested after 7 days' survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM₃CSK₄-injected animals showed significantly more brain injury than vehicle animals (p = 0.014). Compared to NT, HT significantly reduced injury in the PAM₃CSK₄-injected animals, with reduced area loss (p < 0.001), reduced microglial activation (p = 0.006), and increased neuronal rescue in the CA1 region (p < 0.001). Experimental induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to HI injury. HT was highly neuroprotective after the PAM₃CSK₄-triggered injury, suggesting HT may be neuroprotective in the presence of a gram-positive infection. These results are in strong contrast to LPS studies where HT is not neuroprotective.

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Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?)

Abstract: Our results demonstrated that several newborns with an initial mild encephalopathy developed subsequent brain injury, especially when they were not cooled.

Cited by 64 publications

References 27 publications

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy

Prospective research on infants with mild encephalopathy: the PRIME study

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

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