Abstract
Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.
Journal Section:
Editor's choice
References
1.
Perlman M, Shah PS: Hypoxic-ischemic encephalopathy: challenges in outcome and prediction. J Pediatr 2011;158:e51-e54.
[PubMed]
2.
Ferriero DM: Neonatal brain injury. N Engl J Med 2004;351:1985-1995.
[PubMed]
3.
Groenendaal F, Casaer A, Dijkman KP, Gavilanes AW, de Haan TR, ter Horst HJ, Laroche S, Naulaers G, Rijken M, van Straaten HL, Steiner K, Swarte RM, Zecic A, Zonnenberg IA: Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders. Neonatology 2013;104:15-21.
[PubMed]
4.
Grether JK, Nelson KB: Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278:207-211.
[PubMed]
5.
Impey L, Greenwood C, MacQuillan K, Reynolds M, Sheil O: Fever in labour and neonatal encephalopathy: a prospective cohort study. BJOG 2001;108:594-597.
[PubMed]
6.
Blume HK, Li CI, Loch CM, Koepsell TD: Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case-control study. Dev Med Child Neurol 2008;50:19-24.
[PubMed]
7.
Hayes BC, Cooley S, Donnelly J, Doherty E, Grehan A, Madigan C, McGarvey C, Mulvany S, Ryan S, Gillian J, Geary MP, Matthews TG, King MD: The placenta in infants >36 weeks gestation with neonatal encephalopathy: a case control study. Arch Dis Child Fetal Neonatal Ed 2013;98:F233-F239.
[PubMed]
8.
Peebles DM, Wyatt JS: Synergy between antenatal exposure to infection and intrapartum events in causation of perinatal brain injury at term. BJOG 2002;109:737-739.
[PubMed]
9.
Wintermark P, Boyd T, Gregas MC, Labrecque M, Hansen A: Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. Am J Obstet Gynecol 2010;203:579.e1-e9.
[PubMed]
10.
Harteman JC, Nikkels PG, Benders MJ, Kwee A, Groenendaal F, de Vries LS: Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury. J Pediatr 2013;163:968-995.e2.
[PubMed]
11.
Shalak LF, Laptook AR, Jafri HS, Ramilo O, Perlman JM: Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants. Pediatrics 2002;110:673-680.
[PubMed]
12.
Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 2006;124:783-801.
[PubMed]
13.
Wang X, Rousset CI, Hagberg H, Mallard C: Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin Fetal Neonatal Med 2006;11:343-353.
[PubMed]
14.
Rice JE 3rd, Vannucci RC, Brierley JB: The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 1981;9:131-141.
[PubMed]
15.
Eklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I, Hagberg H: Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury. Eur J Neurosci 2001;13:1101-1106.
[PubMed]
16.
Kendall GS, Hristova M, Horn S, Dafou D, Acosta-Saltos A, Almolda B, Zbarsky V, Rumajogee P, Heuer H, Castellano B, Pfeffer K, Nedospasov SA, Peebles DM, Raivich G: TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult. Lab Invest 2011;91:328-341.
[PubMed]
17.
Mallard C: Innate immune regulation by toll-like receptors in the brain. ISRN Neurol 2012;2012:701950.
[PubMed]
18.
Coumans AB, Middelanis JS, Garnier Y, Vaihinger HM, Leib SL, von Duering MU, Hasaart TH, Jensen A, Berger R: Intracisternal application of endotoxin enhances the susceptibility to subsequent hypoxic-ischemic brain damage in neonatal rats. Pediatr Res 2003;53:770-775.
[PubMed]
19.
Eklind S, Mallard C, Arvidsson P, Hagberg H: Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res 2005;58:112-116.
[PubMed]
20.
Wang X, Hagberg H, Nie C, Zhu C, Ikeda T, Mallard C: Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia. J Neuropathol Exp Neurol 2007;66:552-561.
[PubMed]
21.
Yang L, Sameshima H, Ikeda T, Ikenoue T: Lipopolysaccharide administration enhances hypoxic-ischemic brain damage in newborn rats. J Obstet Gynaecol Res 2004;30:142-147.
[PubMed]
22.
Filgueiras CC, Manhaes AC: Increased lateralization in rotational side preference in male mice rendered acallosal by prenatal gamma irradiation. Behav Brain Res 2005;162:289-298.
[PubMed]
23.
van Velthoven CT, van de Looij Y, Kavelaars A, Zijlstra J, van Bel F, Huppi PS, Sizonenko S, Heijnen CJ: Mesenchymal stem cells restore cortical rewiring after neonatal ischemia in mice. Ann Neurol 2012;71:785-796.
[PubMed]
24.
Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S: Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998;57:1-9.
[PubMed]
25.
Sasaki Y, Ohsawa K, Kanazawa, Kohsaka S, Imai Y: Iba1 is an actin-cross-linking protein in macrophages/microglia. Biochem Biophys Res Commun 2001;286:292-297.
[PubMed]
26.
Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y: Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 2001;32:1208-1215.
[PubMed]
27.
Dammann O, Leviton A: Inflammatory brain damage in preterm newborns - dry numbers, wet lab, and causal inferences. Early Hum Dev 2004;79:1-15.
[PubMed]
28.
Hagberg H, Gressens P, Mallard C: Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 2012;71:444-457.
[PubMed]
29.
Volpe JJ: Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 2009;8:110-124.
[PubMed]
30.
Leviton A, Paneth N, Reuss ML, Susser M, Allred EN, Dammann O, Kuban K, Van Marter LJ, Pagano M, Hegyi T, Hiatt M, Sanocka U, Shahrivar F, Abiri M, Disalvo D, Doubilet P, Kairam R, Kazam E, Kirpekar M, Rosenfeld D, Schonfeld S, Share J, Collins M, Genest D, Shen-Schwarz S: Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Pediatr Res 1999;46:566-575.
[PubMed]
31.
Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB: Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290:2677-2684.
[PubMed]
32.
Yoon BH, Park CW, Chaiworapongsa T: Intrauterine infection and the development of cerebral palsy. BJOG 2003;110(suppl 20):124-127.
[PubMed]
33.
Ratnayake U, Quinn T, LaRosa DA, Dickinson H, Walker DW: Prenatal exposure to the viral mimetic poly I:C alters fetal brain cytokine expression and postnatal behaviour. Dev Neurosci 2014;36:83-94.
[PubMed]
34.
Bergeron JD, Deslauriers J, Grignon S, Fortier LC, Lepage M, Stroh T, Poyart C, Sébire G: White matter injury and autistic-like behavior predominantly affecting male rat offspring exposed to group B streptococcal maternal inflammation. Dev Neurosci 2013;35:504-515.
[PubMed]
35.
Balakrishnan B, Dai H, Janisse J, Romero R, Kannan S: Maternal endotoxin exposure results in abnormal neuronal architecture in the newborn rabbit. Dev Neurosci 2013;35:396-405.
[PubMed]
36.
Eklind S, Hagberg H, Wang X, Savman K, Leverin AL, Hedtjarn M, Mallard C: Effect of lipopolysaccharide on global gene expression in the immature rat brain. Pediatr Res 2006;60:161-168.
[PubMed]
37.
Wang X, Stridh L, Li W, Dean J, Elmgren A, Gan L, Eriksson K, Hagberg H, Mallard C: Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner. J Immunol 2009;183:7471-7477.
[PubMed]
38.
Degos V, Peineau S, Nijboer C, Kaindl AM, Sigaut S, Favrais G, Plaisant F, Teissier N, Gouadon E, Lombet A, Saliba E, Collingridge GL, Maze M, Nicoletti F, Heijnen C, Mantz J, Kavelaars A, Gressens P: G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration. Ann Neurol 2013;73:667-678.
[PubMed]
39.
Nijboer CH, Heijnen CJ, Degos V, Willemen HL, Gressens P, Kavelaars A: Astrocyte GRK2 as a novel regulator of glutamate transport and brain damage. Neurobiol Dis 2013;54:206-215.
[PubMed]
40.
Singh AK, Jiang Y: How does peripheral lipopolysaccharide induce gene expression in the brain of rats? Toxicology 2004;201:197-207.
[PubMed]
41.
Xaio H, Banks WA, Niehoff ML, Morley JE: Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res 2001;896:36-42.
[PubMed]
42.
Donega V, van Velthoven CT, Nijboer CH, van Bel F, Kas MJ, Kavelaars A, Heijnen CJ: Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One 2013;8:e51253.
[PubMed]
43.
van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ: Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun 2010;24:387-393.
[PubMed]
44.
Chang YS, Mu D, Wendland M, Sheldon RA, Vexler ZS, McQuillen PS, Ferriero DM: Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res 2005;58:106-111.
[PubMed]
45.
Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE: A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics 2008;122:383-391.
[PubMed]
46.
Welin AK, Svedin P, Lapatto R, Sultan B, Hagberg H, Gressens P, Kjellmer I, Mallard C: Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr Res 2007;61:153-158.
[PubMed]
47.
Fan X, Heijnen CJ, van der Kooij MA, Groenendaal F, van Bel F: Beneficial effect of erythropoietin on sensorimotor function and white matter after hypoxia-ischemia in neonatal mice. Pediatr Res 2011;69:56-61.
[PubMed]
48.
Tusor N, Wusthoff C, Smee N, Merchant N, Arichi T, Allsop JM, Cowan FM, Azzopardi D, Edwards AD, Counsell SJ: Prediction of neurodevelopmental outcome after hypoxic-ischemic encephalopathy treated with hypothermia by diffusion tensor imaging analyzed using tract-based spatial statistics. Pediatr Res 2012;72:63-69.
[PubMed]
49.
Caldu X, Narberhaus A, Junque C, Gimenez M, Vendrell P, Bargallo N, Segarra D, Botet F: Corpus callosum size and neuropsychologic impairment in adolescents who were born preterm. J Child Neurol 2006;21:406-410.
[PubMed]
50.
van Kooij BJ, van Handel M, Uiterwaal CS, Groenendaal F, Nievelstein RA, Rademaker KJ, Jongmans MJ, DE Vries LS: Corpus callosum size in relation to motor performance in 9- to 10-year-old children with neonatal encephalopathy. Pediatr Res 2008;63:103-108.
[PubMed]
51.
van Kooij BJ, de Vries LS, Ball G, van Haastert IC, Benders MJ, Groenendaal F, Counsell SJ: Neonatal tract-based spatial statistics findings and outcome in preterm infants. AJNR Am J Neuroradiol 2012;33:188-194.
[PubMed]
52.
Ewing-Cobbs L, Prasad MR, Swank P, Kramer L, Cox CS Jr, Fletcher JM, Barnes M, Zhang X, Hasan KM: Arrested development and disrupted callosal microstructure following pediatric traumatic brain injury: relation to neurobehavioral outcomes. Neuroimage 2008;42:1305-1315.
[PubMed]
53.
Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA: The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int J Dev Neurosci 2011;29:423-440.
[PubMed]
54.
Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, Arvin KL, Holtzman DM: Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 2002;22:455-463.
[PubMed]
55.
Huang Z, Liu J, Cheung PY, Chen C: Long-term cognitive impairment and myelination deficiency in a rat model of perinatal hypoxic-ischemic brain injury. Brain Res 2009;1301:100-109.
[PubMed]
56.
Buser JR, Maire J, Riddle A, Gong X, Nguyen T, Nelson K, Luo NL, Ren J, Struve J, Sherman LS, Miller SP, Chau V, Hendson G, Ballabh P, Grafe MR, Back SA: Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 2012;71:93-109.
[PubMed]
57.
Billiards SS, Haynes RL, Folkerth RD, Borenstein NS, Trachtenberg FL, Rowitch DH, Ligon KL, Volpe JJ, Kinney HC: Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol 2008;18:153-163.
[PubMed]
58.
Dean JM, van de Looij Y, Sizonenko SV, Lodygensky GA, Lazeyras F, Bolouri H, Kjellmer I, Huppi PS, Hagberg H, Mallard C: Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep. Ann Neurol 2011;70:846-856.
[PubMed]
59.
Hagberg H, Peebles D, Mallard C: Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 2002;8:30-38.
[PubMed]
60.
Duncan JR, Cock ML, Scheerlinck JP, Westcott KT, McLean C, Harding R, Rees SM: White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 2002;52:941-949.
[PubMed]
61.
Garnier Y, Berger R, Alm S, von Duering MU, Coumans AB, Michetti F, Bruschettini M, Lituania M, Hasaart TH, Gazzolo D: Systemic endotoxin administration results in increased S100B protein blood levels and periventricular brain white matter injury in the preterm fetal sheep. Eur J Obstet Gynecol Reprod Biol 2006;124:15-22.
[PubMed]
62.
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.
[PubMed]
63.
Pang Y, Cai Z, Rhodes PG: Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 2003;140:205-214.
[PubMed]
64.
Falahati S, Breu M, Waickman AT, Phillips AW, Arauz EJ, Snyder S, Porambo M, Goeral K, Comi AM, Wilson MA, Johnston MV, Fatemi A: Ischemia-induced neuroinflammation is associated with disrupted development of oligodendrocyte progenitors in a model of periventricular leukomalacia. Dev Neurosci 2013;35:182-196.
[PubMed]
65.
Segovia KN, McClure M, Moravec M, Luo NL, Wan Y, Gong X, Riddle A, Craig A, Struve J, Sherman LS, Back SA: Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury. Ann Neurol 2008;63:520-530.
[PubMed]
66.
Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, Luo NL, Banine F, Liu Y, Chang A, Trapp BD, Bebo BF Jr, Rao MS, Sherman LS: Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 2005;11:966-972.
[PubMed]
67.
Kadhim H, Tabarki B, Verellen G, de Prez C, Rona AM, Sebire G: Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurology 2001;56:1278-1284.
[PubMed]
68.
Pang Y, Campbell L, Zheng B, Fan L, Cai Z, Rhodes P: Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development. Neuroscience 2010;166:464-475.
[PubMed]
69.
Paintlia MK, Paintlia AS, Singh AK, Singh I: Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis. J Neurochem 2011;116:508-521.
[PubMed]
70.
Selmaj K, Raine CS, Farooq M, Norton WT, Brosnan CF: Cytokine cytotoxicity against oligodendrocytes: apoptosis induced by lymphotoxin. J Immunol 1991;147:1522-1529.
[PubMed]
71.
Nijboer CH, Heijnen CJ, Groenendaal F, van Bel F, Kavelaars A: Alternate pathways preserve tumor necrosis factor-α production after nuclear factor-κB inhibition in neonatal cerebral hypoxia-ischemia. Stroke 2009;40:3362-3368.
[PubMed]
72.
Nobuta H, Ghiani CA, Paez PM, Spreuer V, Dong H, Korsak RA, Manukyan A, Li J, Vinters HV, Huang EJ, Rowitch DH, Sofroniew MV, Campagnoni AT, de Vellis J, Waschek JA: STAT3-mediated astrogliosis protects myelin development in neonatal brain injury. Ann Neurol 2012;72:750-765.
[PubMed]
73.
Rodts-Palenik S, Wyatt-Ashmead J, Pang Y, Thigpen B, Cai Z, Rhodes P, Martin JN, Granger J, Bennett WA: Maternal infection-induced white matter injury is reduced by treatment with interleukin-10. Am J Obstet Gynecol 2004;191:1387-1392.
[PubMed]
74.
Brehmer F, Bendix I, Prager S, van de Looij Y, Reinboth BS, Zimmermanns J, Schlager GW, Brait D, Sifringer M, Endesfelder S, Sizonenko S, Mallard C, Buhrer C, Felderhoff-Mueser U, Gerstner B: Interaction of inflammation and hyperoxia in a rat model of neonatal white matter damage. PLoS One 2012;7:e49023.
[PubMed]
75.
Pang Y, Rodts-Palenik S, Cai Z, Bennett WA, Rhodes PG: Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury. Brain Res Dev Brain Res 2005;157:141-149.
[PubMed]
76.
Barres BA, Schmid R, Sendnter M, Raff MC: Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 1993;118:283-295.
[PubMed]
77.
Wolswijk G, Riddle PN, Noble M: Platelet-derived growth factor is mitogenic for O-2Aadult progenitor cells. Glia 1991;4:495-503.
[PubMed]
78.
Dean JM, Wang X, Kaindl AM, Gressens P, Fleiss B, Hagberg H, Mallard C: Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro. Brain Behav Immun 2010;24:776-783.
[PubMed]
79.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 2003;100:8514-8519.
[PubMed]
80.
Vroon A, Heijnen CJ, Lombardi MS, Cobelens PM, Mayor F Jr, Caron MG, Kavelaars A: Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4. J Leukoc Biol 2004;75:901-909.
[PubMed]
81.
Vroon A, Kavelaars A, Limmroth V, Lombardi MS, Goebel MU, van Dam AM, Caron MG, Schedlowski M, Heijnen CJ: G protein-coupled receptor kinase 2 in multiple sclerosis and experimental autoimmune encephalomyelitis. J Immunol 2005;174:4400-4406.
[PubMed]
82.
Hudome S, Palmer C, Roberts RL, Mauger D, Housman C, Towfighi J: The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 1997;41:607-616.
[PubMed]
83.
Nijboer CH, Kavelaars A, Vroon A, Groenendaal F, van Bel F, Heijnen CJ: Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage. J Neurosci 2008;28:3324-3332.
[PubMed]
84.
Palmer C, Roberts RL, Young PI: Timing of neutrophil depletion influences long-term neuroprotection in neonatal rat hypoxic-ischemic brain injury. Pediatr Res 2004;55:549-556.
[PubMed]
85.
Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P, TOBY Study Group: Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349-1358.
[PubMed]
86.
Johnston MV, Fatemi A, Wilson MA, Northington F: Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372-382.
[PubMed]
87.
Osredkar D, Thoresen M, Maes E, Flatebo T, Elstad M, Sabir H: Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 2014;85:567-572.
[PubMed]
© 2015 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2015
You do not currently have access to this content.
