Original article| Volume 40, ISSUE 8, P649-661, September 2018

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Relationship between prolonged neural suppression and cerebral hemodynamic dysfunction during hypothermia in asphyxiated piglets



      Hypothermia (HT) improves the outcome of neonatal hypoxic-ischemic encephalopathy. Here, we investigated changes during HT in cortical electrical activity using amplitude-integrated electroencephalography (aEEG) and in cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation using near-infrared time-resolved spectroscopy (TRS) and compared the results with those obtained during normothermia (NT) after a hypoxic-ischemic (HI) insult in a piglet model of asphyxia. We previously reported that a greater increase in CBV can indicate greater pressure-passive cerebral perfusion due to more severe brain injury and correlates with prolonged neural suppression during NT. We hypothesized that when energy metabolism is suppressed during HT, the cerebral hemodynamics of brains with severe injury would be suppressed to a greater extent, resulting in a greater decrease in CBV during HT that would correlate with prolonged neural suppression after insult.


      Twenty-six piglets were divided into four groups: control with NT (C-NT, n = 3), control with HT (C-HT, n = 3), HI insult with NT (HI-NT, n = 10), and HI insult with HT (HI-HT, n = 10). TRS and aEEG were performed in all groups until 24 h after the insult. Piglets in the HI-HT group were maintained in a hypothermic state for 24 h after the insult.


      There was a positive linear correlation between changes in CBV at 1, 3, 6, and 12 h after the insult and low-amplitude aEEG (<5 µV) duration after insult in the HI-NT group, but a negative linear correlation between these two parameters at 6 and 12 h after the insult in the HI-HT group. The aEEG background score and low-amplitude EEG duration after the insult did not differ between these two groups.

      Discussion and conclusion

      A longer low-amplitude EEG duration after insult was associated with a greater CBV decrease during HT in the HI-HT group, suggesting that brains with more severe neural suppression could be more prone to HT-induced suppression of cerebral metabolism and circulation.


      aEEG (amplitude-integrated electroencephalography), CBF (cerebral blood flow), CBV (cerebral blood volume), CMRO2 (rate of cerebral metabolism of oxygen), HI (hypoxic-ischemic), HIE (hypoxic-ischemic encephalopathy), HR (heart rate), HT (hypothermia), LAEEG (low-amplitude electroencephalography), NIRS (near-infrared spectroscopy), NT (normothermia), PaO2 (arterial oxygen tension), ScO2 (cerebral hemoglobin oxygen saturation), TRS (time-resolved spectroscopy)


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        • Lee A.C.
        • Kozuki N.
        • Blencowe H.
        • Vos T.
        • Bahalim A.
        • Darmstadt G.L.
        • et al.
        Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.
        Pediatric Res. 2013; 74: 50-72
        • Badawi N.
        • Kurinczuk J.J.
        • Keogh J.M.
        • Alessandri L.M.
        • O'Sullivan F.
        • Burton P.R.
        • et al.
        Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study.
        BMJ (Clin Res ed). 1998; 317: 1554-1558
        • Badawi N.
        • Kurinczuk J.J.
        • Keogh J.M.
        • Alessandri L.M.
        • O'Sullivan F.
        • Burton P.R.
        • et al.
        Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
        BMJ (Clinical research ed). 1998; 317: 1549-1553
        • Pierrat V.
        • Haouari N.
        • Liska A.
        • Thomas D.
        • Subtil D.
        • Truffert P.
        • et al.
        Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study.
        Arch Disease Childhood Fetal Neonatal Ed. 2005; 90: F257-F261
        • Hayakawa M.
        • Ito Y.
        • Saito S.
        • Mitsuda N.
        • Hosono S.
        • Yoda H.
        • et al.
        Incidence and prediction of outcome in hypoxic-ischemic encephalopathy in Japan.
        Pediatrics Int. 2014; 56: 215-221
        • Wyllie J.
        • Bruinenberg J.
        • Roehr C.C.
        • Rudiger M.
        • Trevisanuto D.
        • Urlesberger B.
        European Resuscitation Council Guidelines for Resuscitation 2015: Section 7. Resuscitation and support of transition of babies at birth.
        Resuscitation. 2015; 95: 249-263
        • Wyckoff M.H.
        • Aziz K.
        • Escobedo M.B.
        • Kapadia V.S.
        • Kattwinkel J.
        • Perlman J.M.
        • et al.
        Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care.
        Circulation. 2015; 132: S543-S560
        • Jacobs S.E.
        • Berg M.
        • Hunt R.
        • Tarnow-Mordi W.O.
        • Inder T.E.
        • Davis P.G.
        Cooling for newborns with hypoxic ischaemic encephalopathy.
        Cochrane Database Systematic Rev. 2013; (CD003311)
        • Gluckman P.D.
        • Wyatt J.S.
        • Azzopardi D.
        • Ballard R.
        • Edwards A.D.
        • Ferriero D.M.
        • et al.
        Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
        Lancet (London, England). 2005; 365: 663-670
        • Edwards A.D.
        • Brocklehurst P.
        • Gunn A.J.
        • Halliday H.
        • Juszczak E.
        • Levene M.
        • et al.
        Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data.
        BMJ (Clin Res ed). 2010; 340: c363
        • Bonifacio S.L.
        • deVries L.S.
        • Groenendaal F.
        Impact of hypothermia on predictors of poor outcome: how do we decide to redirect care?.
        Seminars Fetal Neonatal Med. 2015; 20: 122-127
        • Toet M.C.
        • Hellstrom-Westas L.
        • Groenendaal F.
        • Eken P.
        • de Vries L.S.
        Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy.
        Arch Disease Childhood Fetal Neonatal Ed. 1999; 81: F19-F23
        • Sarkar S.
        • Barks J.D.
        • Donn S.M.
        Should amplitude-integrated electroencephalography be used to identify infants suitable for hypothermic neuroprotection?.
        J Perinatol. 2008; 28: 117-122
        • Merchant N.
        • Azzopardi D.
        Early predictors of outcome in infants treated with hypothermia for hypoxic-ischaemic encephalopathy.
        Dev Med Child Neurol. 2015; 57: 8-16
        • Thoresen M.
        • Hellstrom-Westas L.
        • Liu X.
        • de Vries L.S.
        Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia.
        Pediatrics. 2010; 126: e131-e139
        • Ancora G.
        • Maranella E.
        • Grandi S.
        • Sbravati F.
        • Coccolini E.
        • Savini S.
        • et al.
        Early predictors of short term neurodevelopmental outcome in asphyxiated cooled infants. A combined brain amplitude integrated electroencephalography and near infrared spectroscopy study.
        Brain Dev. 2013; 35: 26-31
        • Toet M.C.
        • Lemmers P.M.
        • van Schelven L.J.
        • van Bel F.
        Cerebral oxygenation and electrical activity after birth asphyxia: their relation to outcome.
        Pediatrics. 2006; 117: 333-339
        • Nakamura S.
        • Koyano K.
        • Jinnai W.
        • Hamano S.
        • Yasuda S.
        • Konishi Y.
        • et al.
        Simultaneous measurement of cerebral hemoglobin oxygen saturation and blood volume in asphyxiated neonates by near-infrared time-resolved spectroscopy.
        Brain Dev. 2015; 37: 925-932
        • Nakamura M.
        • Jinnai W.
        • Hamano S.
        • Nakamura S.
        • Koyano K.
        • Chiba Y.
        • et al.
        Cerebral blood volume measurement using near-infrared time-resolved spectroscopy and histopathological evaluation after hypoxic-ischemic insult in newborn piglets.
        Int J Dev Neurosci. 2015; 42: 1-9
        • Nakamura S.
        • Kusaka T.
        • Koyano K.
        • Miki T.
        • Ueno M.
        • Jinnai W.
        • et al.
        Relationship between early changes in cerebral blood volume and electrocortical activity after hypoxic-ischemic insult in newborn piglets.
        Brain Dev. 2014; 36: 563-571
        • Gavilanes A.W.
        • Vles J.S.
        • von Siebenthal K.
        • Reulen J.P.
        • Nieman F.H.
        • van Sprundel R.
        • et al.
        Electrocortical brain activity, cerebral haemodynamics and oxygenation during progressive hypotension in newborn piglets.
        Clin Neurophysiol. 2001; 112: 52-59
        • Nakamura S.
        • Kusaka T.
        • Yasuda S.
        • Ueno M.
        • Miki T.
        • Koyano K.
        • et al.
        Cerebral blood volume combined with amplitude-integrated EEG can be a suitable guide to control hypoxic/ischemic insult in a piglet model.
        Brain Dev. 2013; 35: 614-625
        • Ijichi S.
        • Kusaka T.
        • Isobe K.
        • Islam F.
        • Okubo K.
        • Okada H.
        • et al.
        Quantification of cerebral hemoglobin as a function of oxygenation using near-infrared time-resolved spectroscopy in a piglet model of hypoxia.
        J Biomed Optics. 2005; 10: 024026
        • Ijichi S.
        • Kusaka T.
        • Isobe K.
        • Okubo K.
        • Kawada K.
        • Namba M.
        • et al.
        Developmental changes of optical properties in neonates determined by near-infrared time-resolved spectroscopy.
        Pediatr Res. 2005; 58: 568-573
        • Peeters-Scholte C.
        • van den Tweel E.
        • Ioroi T.
        • Post I.
        • Braun K.
        • Veldhuis W.
        • et al.
        Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.
        Exp Brain Res. 2002; 147: 200-208
        • Toet M.C.
        • van der Meij W.
        • de Vries L.S.
        • Uiterwaal C.S.
        • van Huffelen K.C.
        Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates.
        Pediatrics. 2002; 109: 772-779
        • Green J.F.
        • Jackman A.F.
        Mechanism of the increased vascular capacity produced by mild perfusion hypothermia in the dog.
        Med Gas Res. 1979; 44: 411-419
        • Van Bel F.
        • Zeeuwe P.E.
        • Dorrepaal C.A.
        • Benders M.J.
        • Van de Bor M.
        • Hardjowijono R.
        Changes in cerebral hemodynamics and oxygenation during hypothermic cardiopulmonary bypass in neonates and infants.
        Biol. Neonate. 1996; 70: 141-154
        • Okubo K.
        • Itoh S.
        • Isobe K.
        • Kusaka T.
        • Nagano K.
        • Kondo M.
        • et al.
        Cerebral metabolism and regional cerebral blood flow during moderate systemic cooling in newborn piglets.
        Pediatr Int. 2001; 43: 496-501
        • Laptook A.R.
        • Corbett R.J.
        • Sterett R.
        • Garcia D.
        • Tollefsbol G.
        Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy.
        Pediatr Res. 1995; 38: 919-925
        • Bakhsheshi M.F.
        • Diop M.
        • Morrison L.B.
        • St Lawrence K.
        • Lee T.Y.
        Coupling of cerebral blood flow and oxygen consumption during hypothermia in newborn piglets as measured by time-resolved near-infrared spectroscopy: a pilot study.
        Neurophotonics. 2015; 2: 035006
        • Gunn A.J.
        • Gunn T.R.
        • de Haan H.H.
        • Williams C.E.
        • Gluckman P.D.
        Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.
        J Clin Invest. 1997; 99: 248-256