REVIEW URRENT C OPINION
What can you do to protect the newborn brain? Katherine Louise Shea a and Arvind Palanisamy b
Purpose of review Hypoxic-ischemic brain injury is a leading cause of mortality and morbidity in neonates. Treating such injury by interrupting the excitotoxic-oxidative cascade is of immense importance. This review will focus on novel techniques of neuroprotection and describe the latest advances in established therapeutic methods. Key findings Although the primacy of therapeutic hypothermia in treating hypoxic-ischemic encephalopathy is well established, recent research establishes that the arbitrarily chosen regimen of cooling to 338C for 72 h may indeed be the most appropriate method. The optimal duration of antenatal magnesium therapy for neuroprotection remains unsettled, though it is reassuring that even 12 h or less of magnesium therapy results in comparable neurological outcomes. Combining adjuvant therapies such as melatonin or erythropoietin with therapeutic hypothermia results in favorable neurological outcomes compared with hypothermia alone. Finally, stem cell-based therapies show considerable potential in preclinical studies. Summary Significant advances have occurred in the management of neonatal brain injury. With establishment of the optimal temperature and duration of hypothermia, combinatory therapies using adjuncts hold the greatest promise. Promising preclinical approaches such as stem cell-based therapy and use of noble gases need to be confirmed with clinical trials. Keywords fetus, hypothermia, hypoxic-ischemic encephalopathy, magnesium, neuroprotection
INTRODUCTION Optimal development of the human brain is essential for survival, sociability, and optimal functioning in society. Birth and its attendant complications are among the most critical stressors during early brain development; adverse perinatal events disrupt orderly brain development and leave a lasting impact both on individuals and their families. The primary perinatal risk factors associated with newborn brain injury include prematurity, maternal infection, and prolonged hypoxemia-ischemia either as the sole insult or more commonly, in combination with the other two factors [1,2]. In this review, novel neuroprotective techniques and latest advances in previously established neuroprotective strategies will be highlighted. Prevention of prematurity and treatment of maternal infection, though critical to newborn neuroprotection, are beyond the scope of this review. Most research on newborn neuroprotection comes from animal and human models of hypoxic-ischemic encephalopathy (HIE). In developed countries, HIE affects approximately 1–3 per 1000 live term births [2], and neurological disability is more closely correlated to the severity of encephalopathy. Consequences of such injury include
epilepsy, cerebral palsy, mental retardation, and hyperactivity [3–6]. Considering the social and economic burden on the family and society, it is necessary to identify neuroprotective strategies that limit neuronal injury and improve behavioral outcomes. Available strategies target different sites of the excitotoxic-oxidative cascade of neuronal injury and cell death [7], and can be initiated either prior to birth in an at-risk fetus, or immediately after delivery in an already compromised neonate.
ANTENATAL STRATEGIES The best evidence for antenatal neuroprotection is maternal magnesium sulfate administration. a
Clinical Fellow in Obstetric Anesthesia and bAssistant Professor of Anaesthesia, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts, USA Correspondence to Arvind Palanisamy, MD, FRCA, Department of Anesthesiology, Perioperative and Pain Medicine, CWN L1, Brigham and Women’s Hospital, 75 Francis Street Boston, MA 02115, USA. Tel: +1 617 732 8220; fax: +1 617 264 6841; e-mail: [email protected] Curr Opin Anesthesiol 2015, 28:261–266 DOI:10.1097/ACO.0000000000000184
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KEY POINTS Whole body hypothermia to 338C for 72 h is now widely considered the optimal therapeutic option for suspected neonatal brain injury. Combining such treatment with adjuvants such as melatonin or erythropoietin appears to enhance neuroprotection, though further studies are needed. There is solid evidence for maternal magnesium therapy for fetal neuroprotection, and other agents such as allopurinol are being increasingly used for this purpose. Cell regenerative therapy for brain repair is a novel approach, and results from ongoing clinical trials are awaited. The use of noble gases remains experimental at best.
Maternal allopurinol administration and delayed cord clamping may have a salutary benefit.
Maternal magnesium therapy Magnesium is widely administered to women at risk for preterm delivery for neuroprotection of the fetus; maternally administered magnesium easily crosses the placenta and achieves a fetal serum concentration that is approximately 70–100% of the maternal serum levels after a prolonged infusion [8]. In the fetal brain, magnesium exerts a variety of neuroprotective effects, which appear to alleviate the overall excitotoxic damage. For example, magnesium blocks the N-methyl D-aspartate-subtype of glutamate receptor, prevents calcium influx, and limits the increase in intracellular calcium that typically occurs during excitotoxic injury. In addition, it causes cerebral vasodilatation, and ameliorates inflammation-associated brain injury by downregulating cytokines [9]. These effects are believed to contribute to the reduction in the risk of death or cerebral palsy in the offspring of women at risk for delivery within 24 h [10]. Given the familiarity with magnesium and its acceptable safety profile, it is not surprising that numerous professional obstetric societies have widely endorsed its use for fetal neuroprotection. The number needed to prevent one case of death or cerebral palsy with magnesium therapy is between 15 and 35, which makes it an extremely useful obstetric intervention [10]. The exact duration of magnesium therapy, however, is often empirically determined and remains unresolved. To answer this question, McPherson et al. [11 ] performed a secondary cohort analysis of women &
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randomized to receive magnesium sulfate for preterm labor (between 24 and 31 weeks of gestation) in the Maternal-Fetal Medicine Units Network trial. Duration of therapy was categorized into three classes: less than 12 h (N ¼ 356), 12–18 h (N ¼ 341), and moe than 18 h (N ¼ 236). There was no difference in death or cerebral palsy among groups with less than 12 h as reference [Odds ratio (OR) 1.03, 95% CI (confidence interval) 0.60–1.77 for the 12–18 h group, and 1.08, 95% CI 0.57–2.03 in the >18 h group]. Though this study does not establish the optimal duration of magnesium therapy, it suggests that even 12 h or less of magnesium treatment is associated with comparable neuroprotective effects. The use of antenatal magnesium, however, can be associated with an increase in fetal adverse effects such as hypotonia and need for respiratory support during delivery. In a large cohort of 1544 infants born at less than 29 weeks’ gestation, De Jesus et al. [12] compared the risk of adverse cardiorespiratory events in those who were exposed to antenatal magnesium with those who were not. The primary outcome of delivery room intubation or respiratory support at birth or on day 1 after birth was no different between the groups (OR 1.2; 95% CI 0.88–1.65). Interestingly, treatment for hypotension was significantly less in the magnesiumexposed group, though this could be partly explained by the increased use of antenatal steroids and decreased need for invasive mechanical ventilation in the antenatal magnesium group.
Maternal allopurinol Oxidative stress following reperfusion is a major component of preterm brain injury. Allopurinol, a xanthine oxidase inhibitor, limits the toxic overproduction of reactive oxygen species (ROS), and therefore is a promising therapeutic agent. Though there were no differences in long-term neurological outcomes following therapy with 40 mg/kg of intravenous allopurinol in full-term infants suffering from moderate-to-severe asphyxia, a subgroup analysis showed significant reduction in the incidence of severe disabilities in the moderately asphyxiated group [13]. As allopurinol crosses the placenta readily, and reaches therapeutic levels in the fetus [14], there is considerable interest in promoting maternal allopurinol therapy as a potential fetal neuroprotective option. In a multicenter randomized controlled trial involving 222 pregnant women with suspected fetal hypoxia, Kaandorp et al. [15 ] administered either 500-mg allopurinol (N ¼ 111) or placebo (N ¼ 111) intravenously prior to delivery. The primary endpoint, a difference in tissue-specific biomarker for brain damage S100B &
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in cord blood, was no different between the two groups, though there was modest evidence of a beneficial effect in girls. There is a critical need, therefore, to identify the optimal dose and the timing of administration. Another important consequence that remains unstudied is the impact such treatment has on adaptive fetal responses. For example, following fetal hypoxia, ROS interacts with nitric oxide and redistributes fetal cardiac output by preserving cerebral blood flow at the expense of blood flow to the peripheral organs [16]. The impact of allopurinol on this adaptive cardiovascular response needs to be understood before widespread adoption to clinical practice.
Delayed cord clamping Delayed cord clamping (DCC – clamping the umbilical cord at least 0 s after delivery of the fetus) is suggested to decrease the incidence of intraventricular hemorrhage (IVH) in preterm infants by improving oxygen delivery to the brain, decreasing cerebral hypoperfusion, and aiding adequate delivery of clotting factors [17]. In a randomized controlled trial involving 200 preterm neonates born between 24 and 34 weeks’ gestation [18], DCC (N ¼ 99) did not decrease the incidence of periventricular leukomalacia compared with immediate cord clamping (N ¼ 101). However, only 11.1% had IVH in the DCC group compared with 19.8% in the immediate clamp group, though this outcome was not statistically significant (P ¼ 0.09). In term infants, delayed cord clamping (180 s) was not associated with a difference in neurodevelopment, as assessed by parental Ages and Stages Questionnaire, at 12 months of age [19]. Furthermore, in both studies, the effect of DCC on brain injury was not the primary outcome measure. A major limitation in promoting DCC as a neuroprotective strategy in compromised and hypoxemic newborns is the emergent need for resuscitative efforts, which mandates immediate cord clamping and expedited assignment of the neonate to the resuscitation team.
POSTNATAL STRATEGIES Whole body hypothermia with or without the use of adjuncts appears to be the most effective postnatal strategy and the one with best evidence. Stem cellbased therapy is promising, but awaits confirmation from clinical trials.
Therapeutic hypothermia Among all neuroprotective interventions, therapeutic hypothermia is the best established. With
landmark clinical trials showing improvement in neurological outcomes, hypothermia administered within 6 h of neurological injury is widely accepted as viable therapeutic option for term infants with HIE [20,21 ,22,23]. By lowering the temperature of vulnerable deep brain structures to 33–348C, induced hypothermia decreases neuronal apoptosis, attenuates release of excitatory amino acids, reduces cerebral metabolic rate, and lowers the production of nitric oxide and free radicals. In a meta-analysis of 11 RCTs involving 1505 neonates older than 35 weeks’ gestation [24], Jacobs et al. identified a 25% reduction in death and disability with therapeutic hypothermia, with a number needed to benefit (NNTB) of 7. However, this treatment was associated with a 10-fold higher incidence of nonfatal sinus bradycardia and a 20% increase in thrombocytopenia. Recently, whole body hypothermic treatment for neonatal asphyxia was associated with improved neurocognitive outcomes at 6–7 years of age, suggesting that the beneficial effects last longer than previously thought [21 ]. Cooling is typically continued for 72 h, but animal studies suggest that profound hypothermia (to 328C) for a longer duration can be more neuroprotective. Shankaran et al. [25 ] investigated this question in a randomized 2 2 factorial design trial wherein neonates older than 36 weeks’ gestation were assigned to one of four treatments: 33.58C for 72 h, 328C for 72 h, 33.58C for 120 h, or 328C for 120 h. After enrollment of 364 neonates, the trial was prematurely terminated because of the possibility of higher mortality with either prolonged or profound cooling or both. Therefore, the current focus lies in identifying adjunct therapies to augment neuroprotection offered by 72 h of hypothermia at 33–348C. Follow-up studies are required to compare the benefits of whole body cooling with selective head cooling and its impact on neurological outcomes and incidence of adverse effects. In addition, it appears that HIE from hypoxic-ischemic insults in the setting of infection may not respond appropriately to therapeutic hypothermia. In a neonatal rat model of encephalopathy sensitized with lipopolysaccharide injection, hypothermia was not shown to be neuroprotective [26]. &&
&&
&&
Adjuvant therapies Therapeutic hypothermia is only partly effective, and it is estimated that approximately 40–50% of those with moderate-to-severe encephalopathy who receive therapeutic hypothermia will either die or have a severe disability [24]. To address this, many adjuvant therapies have been developed concurrently to supplement hypothermia.
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Melatonin Melatonin (N-acetyl-5-methoxytryptamine), an endogenous indolamine, has antioxidant, antiinflammatory and antiapoptotic properties [27]. In preclinical studies, melatonin is neuroprotective either independently or in concert with therapeutic hypothermia [28,29]. Specifically, it reduces infarct volume, inhibits neuronal cell death, decreases neuronal white matter injury, and decreases sensorimotor asymmetry and learning deficits. Considering that melatonin crosses the blood–brain barrier and the placenta and has minimal side-effects, it is an attractive option for neuroprotection. In a newborn piglet model of perinatal asphyxia, Robertson et al. [29] found that addition of intravenous melatonin to hypothermic neuroprotection improved cerebral energy metabolism, decreased cell death in deep brain structures, and decreased microglial activation in the cortex at 48 h after the insult. In a randomized prospective pilot study in neonates with HIE [30], Aly et al. showed that inclusion of enteral melatonin to hypothermia decreased white matter abnormalities, decreased the incidence of seizures, and enhanced survival without neurological or developmental disabilities at 6 months of age compared with hypothermia alone. As an agent that is well tolerated both in adults and preterm infants [31], melatonin holds considerable promise as an adjunct therapy, though the optimal dose, route, and duration of administration need to be resolved.
hypothermia. Ongoing trials such as the NEAT O (Neonatal Erythropoietin and Therapeutic hypothermia Outcomes) and the NEURPO, a French phase III study, will shed further light on EPO’s utility as a therapeutic adjuvant [33]. Darbepoeitin, an EPO variant with a longer half-life, is another novel adjuvant currently undergoing pharmacokinetic and safety testing (NCT01471015).
Stem cell-based therapy Stem cell-based therapy, popular in the realm of stroke management, is now being explored as a potential option for neurorestoration following HIE [38,39]. Functional recovery is purported to occur via cell replacement (neurogenesis, angiogenesis, synaptogenesis, growth factor secretion) as well as through formation of a biobridge that facilitates endogenous repair mechanisms [40 ]. Cell types with particular promise include neural progenitor cells, mesenchymal stem cells, and umbilical cord mononuclear cells [41,42]. Recently, collection, preparation, and infusion of autologous umbilical cord blood were shown to be feasible in infants with HIE [43 ], suggesting that this modality may become a viable treatment option in the future. In fact, ongoing clinical trials (NCT01962233, NCT00593242) are investigating cell-based therapies for HIE with results anticipated as early as 2015. &&
&
Noble gases Erythropoietin Erythropoietin (EPO), a cytokine, plays important roles during hypoxemic-ischemic injury. Both EPO and its receptor are upregulated during acute hypoxia [32], and EPO serves as a growth factor to promote neurogenesis, oligodendrogenesis, and angiogenesis [33,34]. In addition, EPO facilitates the local response to neuronal injury and provides negative feedback to glial cells limiting extent of injury in areas of penumbra [34]. Hypothermia in combination with EPO improved motor and cognitive outcomes in nonhuman primates exposed to perinatal asphyxia by umbilical cord occlusion [35]. A Phase I dose escalation study in term neonates by Wu et al. found that EPO 1000 U/kg administered intravenously as six doses every 48 h produced optimal neuroprotective EPO plasma concentrations during hypothermia [36]. A follow-up study of these neonates revealed no deaths and a low rate (4.5%) of moderate-to-severe disability at a median age of 22 months [37]. Although this study had a number of limitations including lack of a control group, it showed that high-dose EPO did not worsen outcomes when combined with therapeutic 264
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Noble gases such as argon, xenon, and helium exert neuroprotective effects both in vitro and in vivo [44–46]. Xenon, in particular, appears to be a valuable adjuvant to hypothermia; in preclinical studies, combinatory therapy with xenon and hypothermia was more neuroprotective than either alone [46]. Administration of xenon, an expensive noble gas, requires a closed-circuit delivery system. Dingley et al. [47] recently showed that xenon administration was possible for up to 18 h in neonates with HIE, with no long-term effects until 18 months of age. Currently, two randomized controlled trials are recruiting neonates to investigate the neuroprotective effects of xenon with therapeutic hypothermia the CoolXenon2 (NCT 01545271) and the TOBY Xe study. Evidence for the use of other noble gases such as argon and helium is accumulating, though most studies are limited to the preclinical setting [45,48].
Magnesium Though antenatal magnesium therapy is a well established practice, not much is known about Volume 28 Number 3 June 2015
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What can you do to protect the newborn brain? Shea and Palanisamy
the effects of magnesium when administered during the postnatal period. In a recent meta-analysis, Tagin et al. [49] included randomized controlled trials that compared magnesium with controls in newborns with HIE and found no difference in the incidence of death, moderate-to-severe disability at 18 months, and seizures. Another review of magnesium for perinatal HIE in term models by Galinsky et al. [50] found inconsistent outcomes between studies and identified many confounding variables. The ongoing MagCool trial (NCT01646619) uses magnesium as an adjuvant to hypothermia in the management of term and near-term babies with HIE.
CONCLUSION This review briefly summarizes the latest advances in the management of neonatal brain injury following hypoxemic–ischemic insults. Whole body hypothermia is now a well established therapeutic option, and the ideal temperature and duration of cooling are now settled. Combining hypothermia with other adjuncts now appears to be the next frontier in this field, and there are a few promising candidates such as erythropoietin and melatonin. With advances in the field of cell-based therapy for stroke, there is an increasing interest in using similar therapies for neonatal brain injury. Along with better antenatal recognition of the risk for neonatal brain injury, institution of antenatal neuroprotective therapy, and by decreasing the incidence of preterm birth, more vulnerable brains can be salvaged with these therapies. Acknowledgements None Financial support and sponsorship This work was supported by the Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Boston, USA. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. McIntyre S, Taitz D, Keogh J, et al. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev Med Child Neurol 2013; 55:499–508. 2. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86:329–338.
3. Yager JY, Armstrong EA, Black AM. Treatment of the term newborn with brain injury: simplicity as the mother of invention. Pediatr Neurol 2009; 40:237– 243. 4. Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001; 7:56–64. 5. Low JA. Determining the contribution of asphyxia to brain damage in the neonate. J Obstet Gynaecol Res 2004; 30:276–286. 6. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol 2004; 207:3149–3154. 7. Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011; 10:372–382. 8. Mason BA, Standley CA, Whitty JE, Cotton DB. Fetal ionized magnesium levels parallel maternal levels during magnesium sulfate therapy for preeclampsia. Am J Obstet Gynecol 1996; 175:213–217. 9. Chang JJ, Mack WJ, Saver JL, Sanossian N. Magnesium: potential roles in neurovascular disease. Front Neurol 2014; 5:52. 10. Jacquemyn Y, Zecic A, Van Laere D, Roelens K. The use of intravenous magnesium in nonpreeclamptic pregnant women: fetal/neonatal neuroprotection. Arch Gynecol Obstet 2014. (in press). 11. McPherson JA, Rouse DJ, Grobman WA, et al. Association of duration of & neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes. Obstet Gynecol 2014; 124:749–755. This study reassures that even 12 h of magnesium therapy still confers neuroprotective benefits. 12. De Jesus LC, Sood BG, Shankaran S, et al. Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants. Am J Obstet Gynecol 2015; 212:94; e91-e97. 13. Kaandorp JJ, van Bel F, Veen S, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed 2012; 97:F162–F166. 14. Kaandorp JJ, van den Broek MP, Benders MJ, et al. Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour. Arch Dis Child Fetal Neonatal Ed 2014; 99:F144–F148. 15. Kaandorp JJ, Benders MJ, Schuit E, et al. Maternal allopurinol administration & during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 2014. This is the first trial to investigate allopurinol for fetal neuroprotection. 16. Kane AD, Hansell JA, Herrera EA, et al. Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy. J Physiol 2014; 592:475–489. 17. Salmeen KE, Jelin AC, Thiet MP. Perinatal neuroprotection. F1000Prime Rep 2014; 6:6. 18. Elimian A, Goodman J, Escobedo M, et al. Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial. Obstet Gynecol 2014; 124:1075–1079. 19. Andersson O, Domellof M, Andersson D, Hellstrom-Westas L. Effect of delayed vs early umbilical cord clamping on iron status and neurodevelopment at age 12 months: a randomized clinical trial. JAMA Pediatr 2014; 168:547– 554. 20. Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361:1349– 1358. 21. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal && asphyxia on childhood outcomes. N Engl J Med 2014; 371:140–149. This important trial shows that total body hypothermia confers neurocognitive benefits even at 6–7 years of age. 22. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663–670. 23. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574–1584; This is a landmark trial that confirmed the efficacy of whole body hypothermia for neonatal neuroprotection. 24. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1:CD003311. 25. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of && cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014; 312:2629–2639. This study confirms that the current hypothermia protocol is probably the most appropriate. 26. Osredkar D, Thoresen M, Maes E, et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 2014; 85:567–572. 27. Alonso-Alconada D, Alvarez A, Arteaga O, et al. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia-ischemia. Int J Mol Sci 2013; 14:9379–9395. 28. Carloni S, Perrone S, Buonocore G, et al. Melatonin protects from the longterm consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res 2008; 44:157–164. 29. Robertson NJ, Faulkner S, Fleiss B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 2013; 136:90–105.
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Obstetric and gynecological anesthesia 30. Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 2015; 35:186–191. 31. Merchant NM, Azzopardi DV, Hawwa AF, et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol 2013; 76:725–733. 32. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 2004; 207:3233– 3242; This is an excellent review of the role of erythropoietin in brain repair. 33. Rangarajan V, Juul SE. Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection. Pediatr Neurol 2014; 51:481–488. 34. Marti HH, Bernaudin M, Petit E, Bauer C. Neuroprotection and angiogenesis: dual role of erythropoietin in brain ischemia. News Physiol Sci 2000; 15:225– 229. 35. Traudt CM, McPherson RJ, Bauer LA, et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 2013; 35:491–503. 36. Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 2012; 130:683–691; This study establishes the safety profile and dose range for erythropoeitin therapy in neonates. 37. Rogers EE, Bonifacio SL, Glass HC, et al. Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol 2014; 51:657–662. 38. Comi AM, Cho E, Mulholland JD, et al. Neural stem cells reduce brain injury after unilateral carotid ligation. Pediatr Neurol 2008; 38:86–92. 39. Paula S, Greggio S, DaCosta JC. Use of stem cells in perinatal asphyxia: from bench to bedside. J Pediatr (Rio J) 2010; 86:451–464. 40. Gonzales-Portillo GS, Reyes S, Aguirre D, et al. Stem cell therapy for neonatal && hypoxic-ischemic encephalopathy. Front Neurol 2014; 5:147. This review discusses the rationale and mechanisms driving stem cell-based neurorestorative therapy.
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41. Pimentel-Coelho PM, Mendez-Otero R. Cell therapy for neonatal hypoxicischemic encephalopathy. Stem Cells Dev 2010; 19:299–310. 42. van Velthoven CT, Gonzalez F, Vexler ZS, Ferriero DM. Stem cells for neonatal stroke- the future is here. Front Cell Neurosci 2014; 8:207. 43. Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord & blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 2014; 164:973–979; e971. This study establishes the feasibility of collecting umbilical cord stem cells, laying the foundation for future cell-based therapies for neonatal asphyxia. 44. Jawad N, Rizvi M, Gu J, et al. Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury. Neurosci Lett 2009; 460:232–236. 45. Zhuang L, Yang T, Zhao H, et al. The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats. Crit Care Med 2012; 40:1724– 1730. 46. Lobo N, Yang B, Rizvi M, Ma D. Hypothermia and xenon: novel noble guardians in hypoxic-ischemic encephalopathy? J Neurosci Res 2013; 91:473–478. 47. Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics 2014; 133:809–818. 48. Loetscher PD, Rossaint J, Rossaint R, et al. Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury. Crit Care 2009; 13:R206. 49. Tagin M, Shah PS, Lee KS. Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinatol 2013; 33:663–669. 50. Galinsky R, Bennet L, Groenendaal F, et al. Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in term-equivalent models in preclinical studies: a systematic review. Dev Neurosci 2014; 36:73–82.
Volume 28 Number 3 June 2015
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What can you do to protect the newborn brain? Katherine Louise Shea a and Arvind Palanisamy b
Purpose of review Hypoxic-ischemic brain injury is a leading cause of mortality and morbidity in neonates. Treating such injury by interrupting the excitotoxic-oxidative cascade is of immense importance. This review will focus on novel techniques of neuroprotection and describe the latest advances in established therapeutic methods. Key findings Although the primacy of therapeutic hypothermia in treating hypoxic-ischemic encephalopathy is well established, recent research establishes that the arbitrarily chosen regimen of cooling to 338C for 72 h may indeed be the most appropriate method. The optimal duration of antenatal magnesium therapy for neuroprotection remains unsettled, though it is reassuring that even 12 h or less of magnesium therapy results in comparable neurological outcomes. Combining adjuvant therapies such as melatonin or erythropoietin with therapeutic hypothermia results in favorable neurological outcomes compared with hypothermia alone. Finally, stem cell-based therapies show considerable potential in preclinical studies. Summary Significant advances have occurred in the management of neonatal brain injury. With establishment of the optimal temperature and duration of hypothermia, combinatory therapies using adjuncts hold the greatest promise. Promising preclinical approaches such as stem cell-based therapy and use of noble gases need to be confirmed with clinical trials. Keywords fetus, hypothermia, hypoxic-ischemic encephalopathy, magnesium, neuroprotection
INTRODUCTION Optimal development of the human brain is essential for survival, sociability, and optimal functioning in society. Birth and its attendant complications are among the most critical stressors during early brain development; adverse perinatal events disrupt orderly brain development and leave a lasting impact both on individuals and their families. The primary perinatal risk factors associated with newborn brain injury include prematurity, maternal infection, and prolonged hypoxemia-ischemia either as the sole insult or more commonly, in combination with the other two factors [1,2]. In this review, novel neuroprotective techniques and latest advances in previously established neuroprotective strategies will be highlighted. Prevention of prematurity and treatment of maternal infection, though critical to newborn neuroprotection, are beyond the scope of this review. Most research on newborn neuroprotection comes from animal and human models of hypoxic-ischemic encephalopathy (HIE). In developed countries, HIE affects approximately 1–3 per 1000 live term births [2], and neurological disability is more closely correlated to the severity of encephalopathy. Consequences of such injury include
epilepsy, cerebral palsy, mental retardation, and hyperactivity [3–6]. Considering the social and economic burden on the family and society, it is necessary to identify neuroprotective strategies that limit neuronal injury and improve behavioral outcomes. Available strategies target different sites of the excitotoxic-oxidative cascade of neuronal injury and cell death [7], and can be initiated either prior to birth in an at-risk fetus, or immediately after delivery in an already compromised neonate.
ANTENATAL STRATEGIES The best evidence for antenatal neuroprotection is maternal magnesium sulfate administration. a
Clinical Fellow in Obstetric Anesthesia and bAssistant Professor of Anaesthesia, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts, USA Correspondence to Arvind Palanisamy, MD, FRCA, Department of Anesthesiology, Perioperative and Pain Medicine, CWN L1, Brigham and Women’s Hospital, 75 Francis Street Boston, MA 02115, USA. Tel: +1 617 732 8220; fax: +1 617 264 6841; e-mail: [email protected] Curr Opin Anesthesiol 2015, 28:261–266 DOI:10.1097/ACO.0000000000000184
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KEY POINTS Whole body hypothermia to 338C for 72 h is now widely considered the optimal therapeutic option for suspected neonatal brain injury. Combining such treatment with adjuvants such as melatonin or erythropoietin appears to enhance neuroprotection, though further studies are needed. There is solid evidence for maternal magnesium therapy for fetal neuroprotection, and other agents such as allopurinol are being increasingly used for this purpose. Cell regenerative therapy for brain repair is a novel approach, and results from ongoing clinical trials are awaited. The use of noble gases remains experimental at best.
Maternal allopurinol administration and delayed cord clamping may have a salutary benefit.
Maternal magnesium therapy Magnesium is widely administered to women at risk for preterm delivery for neuroprotection of the fetus; maternally administered magnesium easily crosses the placenta and achieves a fetal serum concentration that is approximately 70–100% of the maternal serum levels after a prolonged infusion [8]. In the fetal brain, magnesium exerts a variety of neuroprotective effects, which appear to alleviate the overall excitotoxic damage. For example, magnesium blocks the N-methyl D-aspartate-subtype of glutamate receptor, prevents calcium influx, and limits the increase in intracellular calcium that typically occurs during excitotoxic injury. In addition, it causes cerebral vasodilatation, and ameliorates inflammation-associated brain injury by downregulating cytokines [9]. These effects are believed to contribute to the reduction in the risk of death or cerebral palsy in the offspring of women at risk for delivery within 24 h [10]. Given the familiarity with magnesium and its acceptable safety profile, it is not surprising that numerous professional obstetric societies have widely endorsed its use for fetal neuroprotection. The number needed to prevent one case of death or cerebral palsy with magnesium therapy is between 15 and 35, which makes it an extremely useful obstetric intervention [10]. The exact duration of magnesium therapy, however, is often empirically determined and remains unresolved. To answer this question, McPherson et al. [11 ] performed a secondary cohort analysis of women &
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randomized to receive magnesium sulfate for preterm labor (between 24 and 31 weeks of gestation) in the Maternal-Fetal Medicine Units Network trial. Duration of therapy was categorized into three classes: less than 12 h (N ¼ 356), 12–18 h (N ¼ 341), and moe than 18 h (N ¼ 236). There was no difference in death or cerebral palsy among groups with less than 12 h as reference [Odds ratio (OR) 1.03, 95% CI (confidence interval) 0.60–1.77 for the 12–18 h group, and 1.08, 95% CI 0.57–2.03 in the >18 h group]. Though this study does not establish the optimal duration of magnesium therapy, it suggests that even 12 h or less of magnesium treatment is associated with comparable neuroprotective effects. The use of antenatal magnesium, however, can be associated with an increase in fetal adverse effects such as hypotonia and need for respiratory support during delivery. In a large cohort of 1544 infants born at less than 29 weeks’ gestation, De Jesus et al. [12] compared the risk of adverse cardiorespiratory events in those who were exposed to antenatal magnesium with those who were not. The primary outcome of delivery room intubation or respiratory support at birth or on day 1 after birth was no different between the groups (OR 1.2; 95% CI 0.88–1.65). Interestingly, treatment for hypotension was significantly less in the magnesiumexposed group, though this could be partly explained by the increased use of antenatal steroids and decreased need for invasive mechanical ventilation in the antenatal magnesium group.
Maternal allopurinol Oxidative stress following reperfusion is a major component of preterm brain injury. Allopurinol, a xanthine oxidase inhibitor, limits the toxic overproduction of reactive oxygen species (ROS), and therefore is a promising therapeutic agent. Though there were no differences in long-term neurological outcomes following therapy with 40 mg/kg of intravenous allopurinol in full-term infants suffering from moderate-to-severe asphyxia, a subgroup analysis showed significant reduction in the incidence of severe disabilities in the moderately asphyxiated group [13]. As allopurinol crosses the placenta readily, and reaches therapeutic levels in the fetus [14], there is considerable interest in promoting maternal allopurinol therapy as a potential fetal neuroprotective option. In a multicenter randomized controlled trial involving 222 pregnant women with suspected fetal hypoxia, Kaandorp et al. [15 ] administered either 500-mg allopurinol (N ¼ 111) or placebo (N ¼ 111) intravenously prior to delivery. The primary endpoint, a difference in tissue-specific biomarker for brain damage S100B &
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in cord blood, was no different between the two groups, though there was modest evidence of a beneficial effect in girls. There is a critical need, therefore, to identify the optimal dose and the timing of administration. Another important consequence that remains unstudied is the impact such treatment has on adaptive fetal responses. For example, following fetal hypoxia, ROS interacts with nitric oxide and redistributes fetal cardiac output by preserving cerebral blood flow at the expense of blood flow to the peripheral organs [16]. The impact of allopurinol on this adaptive cardiovascular response needs to be understood before widespread adoption to clinical practice.
Delayed cord clamping Delayed cord clamping (DCC – clamping the umbilical cord at least 0 s after delivery of the fetus) is suggested to decrease the incidence of intraventricular hemorrhage (IVH) in preterm infants by improving oxygen delivery to the brain, decreasing cerebral hypoperfusion, and aiding adequate delivery of clotting factors [17]. In a randomized controlled trial involving 200 preterm neonates born between 24 and 34 weeks’ gestation [18], DCC (N ¼ 99) did not decrease the incidence of periventricular leukomalacia compared with immediate cord clamping (N ¼ 101). However, only 11.1% had IVH in the DCC group compared with 19.8% in the immediate clamp group, though this outcome was not statistically significant (P ¼ 0.09). In term infants, delayed cord clamping (180 s) was not associated with a difference in neurodevelopment, as assessed by parental Ages and Stages Questionnaire, at 12 months of age [19]. Furthermore, in both studies, the effect of DCC on brain injury was not the primary outcome measure. A major limitation in promoting DCC as a neuroprotective strategy in compromised and hypoxemic newborns is the emergent need for resuscitative efforts, which mandates immediate cord clamping and expedited assignment of the neonate to the resuscitation team.
POSTNATAL STRATEGIES Whole body hypothermia with or without the use of adjuncts appears to be the most effective postnatal strategy and the one with best evidence. Stem cellbased therapy is promising, but awaits confirmation from clinical trials.
Therapeutic hypothermia Among all neuroprotective interventions, therapeutic hypothermia is the best established. With
landmark clinical trials showing improvement in neurological outcomes, hypothermia administered within 6 h of neurological injury is widely accepted as viable therapeutic option for term infants with HIE [20,21 ,22,23]. By lowering the temperature of vulnerable deep brain structures to 33–348C, induced hypothermia decreases neuronal apoptosis, attenuates release of excitatory amino acids, reduces cerebral metabolic rate, and lowers the production of nitric oxide and free radicals. In a meta-analysis of 11 RCTs involving 1505 neonates older than 35 weeks’ gestation [24], Jacobs et al. identified a 25% reduction in death and disability with therapeutic hypothermia, with a number needed to benefit (NNTB) of 7. However, this treatment was associated with a 10-fold higher incidence of nonfatal sinus bradycardia and a 20% increase in thrombocytopenia. Recently, whole body hypothermic treatment for neonatal asphyxia was associated with improved neurocognitive outcomes at 6–7 years of age, suggesting that the beneficial effects last longer than previously thought [21 ]. Cooling is typically continued for 72 h, but animal studies suggest that profound hypothermia (to 328C) for a longer duration can be more neuroprotective. Shankaran et al. [25 ] investigated this question in a randomized 2 2 factorial design trial wherein neonates older than 36 weeks’ gestation were assigned to one of four treatments: 33.58C for 72 h, 328C for 72 h, 33.58C for 120 h, or 328C for 120 h. After enrollment of 364 neonates, the trial was prematurely terminated because of the possibility of higher mortality with either prolonged or profound cooling or both. Therefore, the current focus lies in identifying adjunct therapies to augment neuroprotection offered by 72 h of hypothermia at 33–348C. Follow-up studies are required to compare the benefits of whole body cooling with selective head cooling and its impact on neurological outcomes and incidence of adverse effects. In addition, it appears that HIE from hypoxic-ischemic insults in the setting of infection may not respond appropriately to therapeutic hypothermia. In a neonatal rat model of encephalopathy sensitized with lipopolysaccharide injection, hypothermia was not shown to be neuroprotective [26]. &&
&&
&&
Adjuvant therapies Therapeutic hypothermia is only partly effective, and it is estimated that approximately 40–50% of those with moderate-to-severe encephalopathy who receive therapeutic hypothermia will either die or have a severe disability [24]. To address this, many adjuvant therapies have been developed concurrently to supplement hypothermia.
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Melatonin Melatonin (N-acetyl-5-methoxytryptamine), an endogenous indolamine, has antioxidant, antiinflammatory and antiapoptotic properties [27]. In preclinical studies, melatonin is neuroprotective either independently or in concert with therapeutic hypothermia [28,29]. Specifically, it reduces infarct volume, inhibits neuronal cell death, decreases neuronal white matter injury, and decreases sensorimotor asymmetry and learning deficits. Considering that melatonin crosses the blood–brain barrier and the placenta and has minimal side-effects, it is an attractive option for neuroprotection. In a newborn piglet model of perinatal asphyxia, Robertson et al. [29] found that addition of intravenous melatonin to hypothermic neuroprotection improved cerebral energy metabolism, decreased cell death in deep brain structures, and decreased microglial activation in the cortex at 48 h after the insult. In a randomized prospective pilot study in neonates with HIE [30], Aly et al. showed that inclusion of enteral melatonin to hypothermia decreased white matter abnormalities, decreased the incidence of seizures, and enhanced survival without neurological or developmental disabilities at 6 months of age compared with hypothermia alone. As an agent that is well tolerated both in adults and preterm infants [31], melatonin holds considerable promise as an adjunct therapy, though the optimal dose, route, and duration of administration need to be resolved.
hypothermia. Ongoing trials such as the NEAT O (Neonatal Erythropoietin and Therapeutic hypothermia Outcomes) and the NEURPO, a French phase III study, will shed further light on EPO’s utility as a therapeutic adjuvant [33]. Darbepoeitin, an EPO variant with a longer half-life, is another novel adjuvant currently undergoing pharmacokinetic and safety testing (NCT01471015).
Stem cell-based therapy Stem cell-based therapy, popular in the realm of stroke management, is now being explored as a potential option for neurorestoration following HIE [38,39]. Functional recovery is purported to occur via cell replacement (neurogenesis, angiogenesis, synaptogenesis, growth factor secretion) as well as through formation of a biobridge that facilitates endogenous repair mechanisms [40 ]. Cell types with particular promise include neural progenitor cells, mesenchymal stem cells, and umbilical cord mononuclear cells [41,42]. Recently, collection, preparation, and infusion of autologous umbilical cord blood were shown to be feasible in infants with HIE [43 ], suggesting that this modality may become a viable treatment option in the future. In fact, ongoing clinical trials (NCT01962233, NCT00593242) are investigating cell-based therapies for HIE with results anticipated as early as 2015. &&
&
Noble gases Erythropoietin Erythropoietin (EPO), a cytokine, plays important roles during hypoxemic-ischemic injury. Both EPO and its receptor are upregulated during acute hypoxia [32], and EPO serves as a growth factor to promote neurogenesis, oligodendrogenesis, and angiogenesis [33,34]. In addition, EPO facilitates the local response to neuronal injury and provides negative feedback to glial cells limiting extent of injury in areas of penumbra [34]. Hypothermia in combination with EPO improved motor and cognitive outcomes in nonhuman primates exposed to perinatal asphyxia by umbilical cord occlusion [35]. A Phase I dose escalation study in term neonates by Wu et al. found that EPO 1000 U/kg administered intravenously as six doses every 48 h produced optimal neuroprotective EPO plasma concentrations during hypothermia [36]. A follow-up study of these neonates revealed no deaths and a low rate (4.5%) of moderate-to-severe disability at a median age of 22 months [37]. Although this study had a number of limitations including lack of a control group, it showed that high-dose EPO did not worsen outcomes when combined with therapeutic 264
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Noble gases such as argon, xenon, and helium exert neuroprotective effects both in vitro and in vivo [44–46]. Xenon, in particular, appears to be a valuable adjuvant to hypothermia; in preclinical studies, combinatory therapy with xenon and hypothermia was more neuroprotective than either alone [46]. Administration of xenon, an expensive noble gas, requires a closed-circuit delivery system. Dingley et al. [47] recently showed that xenon administration was possible for up to 18 h in neonates with HIE, with no long-term effects until 18 months of age. Currently, two randomized controlled trials are recruiting neonates to investigate the neuroprotective effects of xenon with therapeutic hypothermia the CoolXenon2 (NCT 01545271) and the TOBY Xe study. Evidence for the use of other noble gases such as argon and helium is accumulating, though most studies are limited to the preclinical setting [45,48].
Magnesium Though antenatal magnesium therapy is a well established practice, not much is known about Volume 28 Number 3 June 2015
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the effects of magnesium when administered during the postnatal period. In a recent meta-analysis, Tagin et al. [49] included randomized controlled trials that compared magnesium with controls in newborns with HIE and found no difference in the incidence of death, moderate-to-severe disability at 18 months, and seizures. Another review of magnesium for perinatal HIE in term models by Galinsky et al. [50] found inconsistent outcomes between studies and identified many confounding variables. The ongoing MagCool trial (NCT01646619) uses magnesium as an adjuvant to hypothermia in the management of term and near-term babies with HIE.
CONCLUSION This review briefly summarizes the latest advances in the management of neonatal brain injury following hypoxemic–ischemic insults. Whole body hypothermia is now a well established therapeutic option, and the ideal temperature and duration of cooling are now settled. Combining hypothermia with other adjuncts now appears to be the next frontier in this field, and there are a few promising candidates such as erythropoietin and melatonin. With advances in the field of cell-based therapy for stroke, there is an increasing interest in using similar therapies for neonatal brain injury. Along with better antenatal recognition of the risk for neonatal brain injury, institution of antenatal neuroprotective therapy, and by decreasing the incidence of preterm birth, more vulnerable brains can be salvaged with these therapies. Acknowledgements None Financial support and sponsorship This work was supported by the Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Boston, USA. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. McIntyre S, Taitz D, Keogh J, et al. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev Med Child Neurol 2013; 55:499–508. 2. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86:329–338.
3. Yager JY, Armstrong EA, Black AM. Treatment of the term newborn with brain injury: simplicity as the mother of invention. Pediatr Neurol 2009; 40:237– 243. 4. Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001; 7:56–64. 5. Low JA. Determining the contribution of asphyxia to brain damage in the neonate. J Obstet Gynaecol Res 2004; 30:276–286. 6. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol 2004; 207:3149–3154. 7. Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011; 10:372–382. 8. Mason BA, Standley CA, Whitty JE, Cotton DB. Fetal ionized magnesium levels parallel maternal levels during magnesium sulfate therapy for preeclampsia. Am J Obstet Gynecol 1996; 175:213–217. 9. Chang JJ, Mack WJ, Saver JL, Sanossian N. Magnesium: potential roles in neurovascular disease. Front Neurol 2014; 5:52. 10. Jacquemyn Y, Zecic A, Van Laere D, Roelens K. The use of intravenous magnesium in nonpreeclamptic pregnant women: fetal/neonatal neuroprotection. Arch Gynecol Obstet 2014. (in press). 11. McPherson JA, Rouse DJ, Grobman WA, et al. Association of duration of & neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes. Obstet Gynecol 2014; 124:749–755. This study reassures that even 12 h of magnesium therapy still confers neuroprotective benefits. 12. De Jesus LC, Sood BG, Shankaran S, et al. Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants. Am J Obstet Gynecol 2015; 212:94; e91-e97. 13. Kaandorp JJ, van Bel F, Veen S, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed 2012; 97:F162–F166. 14. Kaandorp JJ, van den Broek MP, Benders MJ, et al. Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour. Arch Dis Child Fetal Neonatal Ed 2014; 99:F144–F148. 15. Kaandorp JJ, Benders MJ, Schuit E, et al. Maternal allopurinol administration & during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 2014. This is the first trial to investigate allopurinol for fetal neuroprotection. 16. Kane AD, Hansell JA, Herrera EA, et al. Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy. J Physiol 2014; 592:475–489. 17. Salmeen KE, Jelin AC, Thiet MP. Perinatal neuroprotection. F1000Prime Rep 2014; 6:6. 18. Elimian A, Goodman J, Escobedo M, et al. Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial. Obstet Gynecol 2014; 124:1075–1079. 19. Andersson O, Domellof M, Andersson D, Hellstrom-Westas L. Effect of delayed vs early umbilical cord clamping on iron status and neurodevelopment at age 12 months: a randomized clinical trial. JAMA Pediatr 2014; 168:547– 554. 20. Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361:1349– 1358. 21. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal && asphyxia on childhood outcomes. N Engl J Med 2014; 371:140–149. This important trial shows that total body hypothermia confers neurocognitive benefits even at 6–7 years of age. 22. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663–670. 23. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574–1584; This is a landmark trial that confirmed the efficacy of whole body hypothermia for neonatal neuroprotection. 24. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1:CD003311. 25. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of && cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014; 312:2629–2639. This study confirms that the current hypothermia protocol is probably the most appropriate. 26. Osredkar D, Thoresen M, Maes E, et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation 2014; 85:567–572. 27. Alonso-Alconada D, Alvarez A, Arteaga O, et al. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia-ischemia. Int J Mol Sci 2013; 14:9379–9395. 28. Carloni S, Perrone S, Buonocore G, et al. Melatonin protects from the longterm consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res 2008; 44:157–164. 29. Robertson NJ, Faulkner S, Fleiss B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 2013; 136:90–105.
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Obstetric and gynecological anesthesia 30. Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 2015; 35:186–191. 31. Merchant NM, Azzopardi DV, Hawwa AF, et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol 2013; 76:725–733. 32. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 2004; 207:3233– 3242; This is an excellent review of the role of erythropoietin in brain repair. 33. Rangarajan V, Juul SE. Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection. Pediatr Neurol 2014; 51:481–488. 34. Marti HH, Bernaudin M, Petit E, Bauer C. Neuroprotection and angiogenesis: dual role of erythropoietin in brain ischemia. News Physiol Sci 2000; 15:225– 229. 35. Traudt CM, McPherson RJ, Bauer LA, et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 2013; 35:491–503. 36. Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 2012; 130:683–691; This study establishes the safety profile and dose range for erythropoeitin therapy in neonates. 37. Rogers EE, Bonifacio SL, Glass HC, et al. Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol 2014; 51:657–662. 38. Comi AM, Cho E, Mulholland JD, et al. Neural stem cells reduce brain injury after unilateral carotid ligation. Pediatr Neurol 2008; 38:86–92. 39. Paula S, Greggio S, DaCosta JC. Use of stem cells in perinatal asphyxia: from bench to bedside. J Pediatr (Rio J) 2010; 86:451–464. 40. Gonzales-Portillo GS, Reyes S, Aguirre D, et al. Stem cell therapy for neonatal && hypoxic-ischemic encephalopathy. Front Neurol 2014; 5:147. This review discusses the rationale and mechanisms driving stem cell-based neurorestorative therapy.
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41. Pimentel-Coelho PM, Mendez-Otero R. Cell therapy for neonatal hypoxicischemic encephalopathy. Stem Cells Dev 2010; 19:299–310. 42. van Velthoven CT, Gonzalez F, Vexler ZS, Ferriero DM. Stem cells for neonatal stroke- the future is here. Front Cell Neurosci 2014; 8:207. 43. Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord & blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 2014; 164:973–979; e971. This study establishes the feasibility of collecting umbilical cord stem cells, laying the foundation for future cell-based therapies for neonatal asphyxia. 44. Jawad N, Rizvi M, Gu J, et al. Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury. Neurosci Lett 2009; 460:232–236. 45. Zhuang L, Yang T, Zhao H, et al. The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats. Crit Care Med 2012; 40:1724– 1730. 46. Lobo N, Yang B, Rizvi M, Ma D. Hypothermia and xenon: novel noble guardians in hypoxic-ischemic encephalopathy? J Neurosci Res 2013; 91:473–478. 47. Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics 2014; 133:809–818. 48. Loetscher PD, Rossaint J, Rossaint R, et al. Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury. Crit Care 2009; 13:R206. 49. Tagin M, Shah PS, Lee KS. Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinatol 2013; 33:663–669. 50. Galinsky R, Bennet L, Groenendaal F, et al. Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in term-equivalent models in preclinical studies: a systematic review. Dev Neurosci 2014; 36:73–82.
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