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Which Neuroprotective Agents are Ready for Bench to Bedside Translation in the Newborn Infant?

2012; Elsevier BV; Volume: 160; Issue: 4 Linguagem: Inglês

10.1016/j.jpeds.2011.12.052

1097-6833

Nicola J. Robertson, Sidhartha Tan, Floris Groenendaal, Frank van Bel, Sandra E. Juul, Laura Bennet, Matthew Derrick, Stephen A. Back, Raul Chavez‐Valdez, Frances J. Northington, Alistair J. Gunn, Carina Mallard,

Thermal Regulation in Medicine

Neonatal encephalopathy caused by perinatal hypoxia-ischemia in term newborn infants occurs in 1 to 3 per 1000 births1Kurinczuk J. White-Koning M. Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.Early Hum Dev. 2010; 86: 329-338Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar and leads to high mortality and morbidity rates with life-long chronic disabilities.2Marlow N. Rose A. Rands C. Draper E.S. Neuropsychological and educational problems at school age associated with neonatal encephalopathy.Arch Dis Child Fetal Neonatal Ed. 2005; 90: F380-F387Crossref PubMed Scopus (114) Google Scholar, 3Robertson C.M. Finer N.N. Grace M.G. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term.J Pediatr. 1989; 114: 753-760Abstract Full Text PDF PubMed Google Scholar Although therapeutic hypothermia is a significant advance in the developed world and improves outcome,4Edwards A. Brocklehurst P. Gunn A. 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. 2010; 340: C363Crossref PubMed Scopus (237) Google Scholar, 5Gluckman P. Wyatt J. Azzopardi D. Ballard R. Edwards A. Ferriero D. et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.Lancet. 2005; 365: 663-670Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar hypothermia offers just 11% reduction in risk of death or disability, from 58% to 47%. Therefore, there still is an urgent need for other treatment options. Further, there are currently no clinically established interventions that can be given antenatally to ameliorate brain injury after fetal distress. One of the major limitations to progress is what may be called “the curse of choice.” A large number of possible neuroprotective therapies have shown promise in pre-clinical studies.6Kelen D. Robertson N.J. Experimental treatments for hypoxic ischaemic encephalopathy.Early Hum Dev. 2010; 86: 369-377Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 7Cilio M. Ferriero D. Synergistic neuroprotective therapies with hypothermia.Semin Fetal Neonatal Med. 2010; 15: 293-298Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar How should we select from them? There is no consensus at present on which drugs have a high chance of success for either antenatal or postnatal treatment. There are insufficient societal resources available to test them all. Thus, it is imperative to marshal finite resources and prioritize potential therapies for investigation. The authors believe that facilitating discussion of strategy and findings in “competing” laboratories is critical to facilitate efficient progress toward optimizing neuroprotection after hypoxia-ischemia. Few studies have examined possible interactions of medications with hypothermia and whether combination therapies augment neuroprotection. The timing of the administration of medications may be critical to optimize benefit and avoid neurotoxicity (eg, early acute treatments targeted at amelioration of the neurotoxic cascade compared with subacute treatment that can promote regeneration and repair). Intervention early on in the cascade of neural injury is likely to achieve more optimal neuroprotection8Carroll M. Beek O. Protection against hippocampal CA1 cell loss by post-ischaemic hypothermia is dependent on delay of initiation and duration.Metab Brain Dis. 1992; 7: 45-50Crossref PubMed Scopus (108) Google Scholar, 9Gunn A. Gunn T. Gunning M. Williams C. Gluckman P. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.Pediatrics. 1998; 102: 1098-1106Crossref PubMed Scopus (175) Google Scholar; however, there is frequently little warning of impending perinatal hypoxia-ischemia episodes. Sensitizing factors such as maternal pyrexia,10Badawi N. Kurinczuk J.J. Keogh J.M. Alessandri L.M. O’Sullivan F. Burton P.R. Pemberton P.J. Stanley F.J. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study.BMJ. 1998; 317: 1554-1558Crossref PubMed Google Scholar maternal/fetal infection,11Lehnardt S.M.L. Follett P. Jensen F.E. Ratan R. Rosenberg P.A. Volpe J.J. et al.Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.PNAS. 2003; 100: 8514-8519Crossref PubMed Scopus (437) Google Scholar, 12Eklind S. Mallard C. Leverin A.L. Gilland E. Blomgren K. Mattsby-Baltzer I. et al.Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury.Eur J Neurosci. 2001; 13: 1101-1106Crossref PubMed Google Scholar and poor fetal growth13Badawi 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. 1998; 317: 1549-1553Crossref PubMed Google Scholar are well recognized and contribute to the heterogeneity of the fetal response and outcome in neonatal encephalopathy. We include potential antenatal therapy medications in the scoring process; however, electronic fetal monitoring has a low positive predictive value (3%–18%) for identifying intrapartum asphyxia.14Williams K.P. Galerneau F. Comparison of intrapartum fetal heart rate tracings in patients with neonatal seizures vs. no seizures: what are the differences?.J Perinat Med. 2004; 32: 422-425Crossref PubMed Scopus (11) Google Scholar, 15Kumar S. Paterson-Brown S. Obstetric aspects of hypoxic ischemic encephalopathy.Early Hum Dev. 2010; 86: 339-344Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 16Williams K.P. Galerneau F. Intrapartum fetal heart rate patterns in the prediction of neonatal acidemia.Am J Obstet Gynaecol. 2003; 188: 820-823Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Westgate J. Wibbens B. Bennet L. Wassink G. Parer J. Gunn A. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor.Am J Obstet Gynaecol. 2007; 197: 236.e1-236.e11Abstract Full Text Full Text PDF Scopus (17) Google Scholar, 18Vijgen S. Westerhuis M. Opmeer B. Visser G. Moons K. Porath M. et al.Cost-effectiveness of cardiotocography plus ST analysis of the fetal electrocardiogram compared with cardiotocography only.Acta Obstet Gynecol Scand. 2011; 90: 772-778Crossref PubMed Scopus (4) Google Scholar At present, therefore, any antenatal intervention potentially involves treatment of many cases that do not need treatment in order to benefit a few at risk of brain injury. In January 2008, investigators from research institutions with a special interest in neuroprotection of the newborn appraised published evidence about medications that have been used in pre-clinical animal models, pilot clinical studies, or both as treatments for: (1) antenatal therapy for fetuses with a diagnosis of antenatal fetal distress at term; and (2) postnatal therapy of infants with moderate to severe neonatal encephalopathy. The aims of this study were to: (1) prioritize potential treatments for antenatal and postnatal therapy; and (2) provide a balanced reference for further discussions in the perinatal neuroscience community for future research and clinical translation of novel neuroprotective treatments of the newborn. A systematic PubMed search up to June 2011 was undertaken to identify medications with evidence of neuroprotection in pre-clinical studies when given either antenatally or postnatally after perinatal hypoxia-ischemia. For antenatal treatments, each medication was scored to a manual score of 60 by using 6 questions, each ranked 1 to 10: (1) placental transfer; (2) ease of administration; (3) knowledge about starting dose; (4) adverse effects; (5) teratological or toxic effects; and (6) overall benefit and efficacy. For postnatal treatments, each drug was scored to a total possible score of 50 by using 5 questions, each scored 1 to 10: (1) ease of administration; (2) knowledge about starting dose; (3) adverse effects; (4) teratological or toxic effects; and (5) overall benefit and efficacy. The 12 authors represent perinatal neuroscience research groups from The Netherlands, United Kingdom, United States, Sweden, and New Zealand. Two to 3 medications were assigned to each member; each member was asked to evaluate the scientific literature, score the assigned medications, and present this evidence to the group, justifying the scores. General guidance for the scores were: score 0 to 3, no evidence or some significant concerns; score 4 to 5, some evidence or some concerns; score 6 to 8, good evidence or minor concerns; and score 9 to 10, compelling evidence and no significant concerns. Final scores reflected the opinion of the whole group. A total of 5 meetings were held, the first by Skype (Microsoft Skype Division, Luxembourg City, Luxembourg) in January 2009, and the final meeting was held in May 2011. Thirteen neuroprotective medications were identified. The possible mechanisms of action are shown in the Figure. They were classified as US Food and Drug Administration (FDA)-approved (adenosine A2A receptor antagonist, allopurinol, erythropoietin [Epo], melatonin, memantine, N-acetylcysteine [NAC], resveratrol, topiramate, vitamins C & E, tetrahydrobiopterin [BH4]) and non-FDA-approved (Epo-mimetic peptides, neuronal nitric oxide synthase [nNOS] inhibitors, xenon). The medication with the highest score was BH4 (score 54/60, 90%), which was chosen for ease of administration, absence of teratological effects, and potential benefit. Melatonin (49/60, 82%) was the second choice, because of ease of administration and placental transfer and benefit. The medications with the lowest scores were topiramate and memantine (6/60, 10%). nNOS inhibitors were ranked third (75%). Xenon scored 42 of 60 (70%) and was ranked fourth; most points were lost in the “ease of administration” category. Allopurinol was ranked fifth (67%), followed by vitamins C and E (39/60, 65%). NAC, Epo-mimetics, Epo, resveratrol, and adenosine A2A receptor antagonists all scored 80%, and melatonin was still (but less) effective when given 4 hours after the insult39Husson I. Mesplès B. Bac P. Vamecq J. Evrard P. Gressens P. Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge.Ann Neurol. 2002; 51: 82-92Crossref PubMed Scopus (106) Google Scholar and reduced learning deficits.49Bouslama M. Renaud J. Olivier P. Fontaine R.H. Matrot B. Gressens P. et al.Melatonin prevents learning disorders in brain-lesioned newborn mice.Neuroscience. 2007; 150: 712-719Crossref PubMed Scopus (21) Google Scholar Protection of the cerebral white matter has also been shown after 2 hours of hypoxic insults in newborn rats,50Kaur C. Sivakumar V. Ling E. Melatonin protects periventricular white matter from damage due to hypoxia.J Pineal Res. 2010; 48: 185-193Crossref PubMed Scopus (26) Google Scholar and melatonin decreased microglial activation and astroglial reaction and promoted oligodendrocyte maturation in growth restricted rat pups.51Olivier P. Fontaine R.H. Loron G. Van Steenwinckel J. Biran V. Massonneau V. et al.Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats.PLoS One. 2009; 22: e7128Crossref Scopus (30) Google Scholar Furthermore, in a model of lipopolysacchride-induced hypoxic-ischemic injury in neonatal rats, melatonin reduced injury by 45% when given repeatedly at 5 mg/kg, and a higher dose (20 mg/kg) did not significantly protect the brain.52Wang X. Svedin