TY - JOUR
T1 - Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia
AU - Martinello, Kathryn A.
AU - Meehan, Christopher
AU - Avdic-Belltheus, Adnan
AU - Lingam, Ingran
AU - Mutshiya, Tatenda
AU - Yang, Qin
AU - Akin, Mustafa Ali
AU - Price, David
AU - Sokolska, Magdalena
AU - Bainbridge, Alan
AU - Hristova, Mariya
AU - Tachtsidis, Ilias
AU - Tann, Cally J.
AU - Peebles, Donald
AU - Hagberg, Henrik
AU - Wolfs, Tim G.A.M.
AU - Klein, Nigel
AU - Kramer, Boris W.
AU - Fleiss, Bobbi
AU - Gressens, Pierre
AU - Golay, Xavier
AU - Robertson, Nicola J.
N1 - Funding Information:
We thank Debbie Kraus (PRISMTC) for her statistical analysis and Cornelius Bauer (UCL) for his expertise with bNIRS acquisition. This project was supported by a grant from the Medical Research Council (grant number MR/M0067431).
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - Background: Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. Methods: Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. Results: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. Conclusions: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. Impact: Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown.In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death.Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.
AB - Background: Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. Methods: Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. Results: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. Conclusions: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. Impact: Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown.In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death.Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.
UR - http://www.scopus.com/inward/record.url?scp=85106685519&partnerID=8YFLogxK
U2 - 10.1038/s41390-021-01584-6
DO - 10.1038/s41390-021-01584-6
M3 - Article
AN - SCOPUS:85106685519
SN - 0031-3998
JO - Pediatric Research
JF - Pediatric Research
ER -