Pharmacology Review : Neuroprotective Treatments for Hypoxic-Ischemic Injury Peter J.

Marro and Maria Delivoria-Papadopoulos Neoreviews 2010;11;e311 DOI: 10.1542/neo.11-6-e311

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pharmacology review

Neuroprotective Treatments for Hypoxic-Ischemic Injury

Peter J. Marro, MD,* Maria Delivoria-Papadopoulos, MD

Abstract
Although the evidence supporting the efcacy of neuroprotective treatments for hypoxic-ischemic injury in human newborns is limited, efforts to develop effective treatments continue in laboratory studies. In this article, we review some of the treatments that have found their way from the laboratory to clinical studies in newborns. Specically, the evidence for use of magnesium sulfate, allopurinol, opioids, and hypothermia as possible treatments of hypoxic-ischemic encephalopathy are discussed.

Author Disclosure Drs Marro and DelivoriaPapadopoulos have disclosed no nancial relationships relevant to this article. This commentary does contain a discussion of an unapproved/investigative use of a commercial product/device.

Objectives

After completing this article, readers should be able to:

1. Describe the results of trials of magnesium sulfate, allopurinol, and opioids as neuroprotective agents. 2. Explain how hypothermia is used to treat perinatal asphyxia/hypoxicischemic encephalopathy,

Introduction
In our recent article in NeoReviews (2010;11:e184 e193), we discussed the Biochemical Basis for HypoxicIschemic Encephalopathy. The following discussion examines some of the treatments considered as potential neuroprotective strategies in the human newborn exposed to hypoxicischemic brain injury.

Magnesium Sulfate
In the clinical setting, magnesium sulfate (MgSO4) has been used widely in obstetrics practice for more than 60 years. Its indications include suppression of preterm labor and management of pregnancy-induced hypertension. (1) A retrospective epidemiologic study by Nelson and Grether (2) suggested that preterm fetuses whose mothers received
*Division of Neonatology, Barbara Bush Childrens Hospital at Maine Medical Center, Portland, Me. Professor of Pediatrics and Physiology Emeritus, University of Pennsylvania School of Medicine, Philadelphia, Pa.

MgSO4 for the treatment of preeclampsia or as a tocolytic agent are less likely to develop cerebral palsy compared with a gestational agematched group of fetuses not exposed to the drug. The Collaborative Eclampsia Trial (3) reported that babies of women who had been given MgSO4 before delivery were signicantly less likely to be intubated at delivery or to be admitted to a special care nursery than the babies of mothers who had been given phenytoin. These studies suggested that MgSO4 might provide a protective effect against brain damage in immature fetuses and newborns. Randomized, controlled, double-blind trials were established to examine this hypothesis. One was discontinued after interim analysis showed that administration of MgSO4 to mothers in preterm labor before 34 weeks of gestation was associated with a signicant increase in infant mortality. (4) However, other trials have not shown any difference in the mortality
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rates between placebo and treatment groups. (5) A United States multicenter, randomized, controlled trial comparing MgSO4 with placebo for the prevention of cerebral palsy in 2,241 women at risk of imminent premature delivery at 24 to 31 weeks of gestation was published in 2008. (6) The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age. The primary outcome was not signicantly different in the MgSO4 group and the placebo group. However, in a prespecied secondary analysis, moderate or severe cerebral palsy occurred signicantly less frequently in the MgSO4 group (1.9% versus 3.5%). A similar study in France followed 606 infants born at less than 33 weeks of gestation whose mothers were treated with MgSO4. (7) Compared with placebo, treated infants showed a decrease of all primary endpoints (total mortality, severe white matter injury, and their combined outcome) and of all secondary endpoints (motor dysfunction, cerebral palsy, cognitive dysfunction, and their combined outcomes at 2 years of age). The decrease was nearly signicant or signicant for gross motor dysfunction and combined criteria of death and cerebral palsy; death and gross motor dysfunction; and death, cerebral palsy, and cognitive dysfunction. Doyle and associates (8) reviewed the evidence of the neuroprotective effects of MgSO4 administered to women considered at risk of preterm birth. They concluded that the neuroprotective role for antenatal MgSO4 therapy provided to mothers at such risk is now established. The number of women needed to treat to benet one baby by avoiding cerebral palsy is 63 (95% condence interval,
e312 NeoReviews Vol.11 No.6 June 2010

43 to 87). Given the benecial effects of MgSO4 on substantial gross motor function in early childhood, outcomes later in childhood should be evaluated to determine the presence or absence of later potentially important neurologic effects, particularly on motor or cognitive function.

Allopurinol
In experimental animal models, administration of allopurinol to immature rats 30 minutes before inducing focal hypoxia-ischemia reduced the severity of the secondary edema and the extent of the neuropathologic lesion in the treated group compared with a control group. (9) Similarly, pretreatment with allopurinol preserved cerebral energy metabolism of the 7-day postnatal rat during hypoxia-ischemia. (10) The same group of researchers found that oxypurinol, the active metabolite of allopurinol, administered at the same dose and at the same time as allopurinol after hypoxia-ischemia reduced brain injury in the immature rat. (11) Administration of allopurinol in newborn piglets prevented the hypoxia-induced modication of NMDA receptors as well as cell membrane peroxidation and neuronal dysfunction. (12)(13) In the clinical setting, a 7-day course of enteral allopurinol (20 mg/kg) administered after birth to 400 infants between 24 and 32 weeks gestation did not change the incidence of periventricular leukomalacia. (14) In a study of 22 asphyxiated newborns, intravenous allopurinol in a dose of 40 mg/kg administered 4 hours after birth resulted in decreased mortality (2 of 11 versus 6 of 11 in the control group) and in a benecial effect on free radical formation, cerebral blood ow, and electrical brain activity without toxic adverse effects. (15) Clancy and associates (16) conducted a clinical

trial to test the hypothesis that allopurinol could reduce the incidence of death, seizures, coma, and cardiac events in infants who underwent heart surgery using deep hypothermic circulatory arrest. They studied 318 infants, 131 of whom had hypoplastic left heart syndrome (HLHS) and 187 of whom did not. Among HLHS surgical survivors, 40 of 47 (85%) allopurinol-treated infants did not experience any endpoint event compared with 27 of 49 (55%) controls (P0.002). There were fewer seizure-only (P0.05) and cardiac-only (P0.03) events in the allopurinol versus placebo groups. Allopurinol did not reduce efcacy endpoint events in non-HLHS infants. Treated and control infants did not differ in adverse events. Bender and colleagues (17) investigated whether postnatal allopurinol would reduce free radical-induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates. In an interim analysis of a randomized, double-blind, placebocontrolled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within 4 hours of birth. The analysis showed an unaltered (high) mortality and morbidity in infants treated with allopurinol. The authors concluded that allopurinol treatment started postnatally was too late to reduce the early reperfusioninduced free radical surge. Allopurinol administration to the fetus that has (imminent) hypoxia via the mother during labor may be more effective in reducing free radicalinduced postasphyxial brain damage. Chaudhari and McGuire (18) performed a meta-analysis to evaluate the effect of allopurinol on mortality or morbidity in newborns who had suspected hypoxic-ischemic encephalopathy. The authors concluded that the available data are not sufcient to determine whether allopuri-

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nol has clinically important benets for such infants and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants who have moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.

Opioids
The antinociceptive effects of opioids are mediated through a combination of pre- and postsynaptic hyperpolarization, which produces a decrease in the release of and the sensitivity to endogenous mediators such as glutamate. (19)(20) This suggests that they may have a neuroprotective effect. Indeed, studies in cell cultures have demonstrated that endogenous and exogenous opioids may protect cortical neurons from hypoxiainduced cell death. (21)(22) Similarly, opioids may induce ischemic tolerance in cerebellar Purkinje cells subject to ischemia-reperfusion. (23) Antagonists of opioid receptors increase the survival time during severe hypoxia in intact animals (24)(25) and enhance tissue preservation and survival time of organs used for transplantation. (26) In 2005, Angeles and associates (27) published the results of a retrospective study of 52 term newborns who had perinatal asphyxia, in which they analyzed the relationship between treatment with opioid analgesics (morphine or fentanyl) and neurologic damage. Thirty-three percent of the infants received opioids, and despite having more severe degrees of asphyxia (higher concentrations of lactate, lower 5-minute Apgar scores), this group of patients had less severe signs of brain damage on magnetic resonance imaging performed after 7 days of age. Moreover, their neurologic

outcomes at a mean follow-up of 13 months were better than the group of newborns who did not receive opioids. The same group of researchers also performed a follow-up study with magnetic resonance spectroscopy of 28 term newborns treated with opioids and 20 controls. (28) The results showed that occipital gray matter N-acetylaspartate/creatinine was signicantly decreased and lactate was present in a signicantly higher amount in nonopioid-treated neonates compared with opioid-treated neonates. Also, compared with controls, untreated neonates showed large changes in more metabolites in basal ganglia, thalami, and occipital gray matter with greater signicance than treated neonates. The authors concluded that the use of opioids during the rst week following perinatal asphyxia has no long-term adverse effects and may increase brain resistance to hypoxia-ischemia. They speculated that the neuroprotective effect of opioids may be mediated by increasing concentrations of adenosine, an endogenous nucleoside that has neuroprotective activity, or by inducing neuronal hyperpolarization, which results in diminishing intracellular penetration of calcium. Despite the potential benet of opioids on asphyxiated term neonates indicated in these studies, this class of medications must be used cautiously. Available literature suggests that the routine use of opioid analgesics can be complicated by problems such as tolerance, withdrawal symptoms, and ventilator dependence. Very few studies have examined the long-term effects of exposure to opioids in the neonatal period. In addition, previous reports indicate that endogenous opioids can suppress DNA synthesis in vivo in mature cerebellar and glial cells (opioid receptors are widely distributed in the central nervous system with

functions that include pain modulation and cardiorespiratory regulation), whereas exogenous opioids can exacerbate neurotoxicity in animal models of cerebral ischemia. Future prospective randomized trials are warranted to determine whether there is truly an immediate neuroprotective effect on hypoxic-ischemic brain injury and whether these agents can play a role in improving longterm outcome.

Hypothermia
Hypothermia has developed during the past few years as an alternative for treating perinatal asphyxia/hypoxicischemic encephalopathy. (29)(30) Hypothermia during experimental cerebral ischemia is associated with potent dose-related, long-lasting neuroprotection. Conversely, hyperthermia of only 1C to 2C extends and markedly worsens damage, and in particular tends to promote pannecrosis. (29) The study of the mechanisms of action of hypothermic neuroprotection suggests that cooling affects many or all of the pathways leading to delayed cell death. (29) Hypothermia reduces the rate of oxygenrequiring enzymatic reactions and cerebral oxygen consumption, slows the decrease in phosphocreatine/ inorganic phosphate (PCr/Pi), and confers a protective effect of the brain after adenosine triphosphate exhaustion. In addition, hypothermia decreases oxygen consumption of the brain by 6% to 7% and cerebral energy utilization rate by 5.3% per degree. Additional experimental evidence suggests that hypothermia suppresses cytotoxic excitatory amino acid accumulation, inhibits nitric oxide synthase activity, decreases interleukin-1 concentrations, decreases the release of other cytotoxic cytokines by microglial cells, and suppresses free radical activity and
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delayed cell death by apoptosis. Hypothermia also decreases blood-brain barrier permeability and intracranial pressure and facilitates recovery of electrophysiologic function after cerebral ischemia. The efcacy of hypothermia is dependent on a number of factors, such as the timing of initiation of cooling, its duration, and the depth of cooling attained. Mild hypothermia is dened as a reduction in core temperature of 1C to 3C, moderate as 4C to 6C, severe as 8C to 10C, and profound as 15C to 20C. Brief (0.5 to 3 hours), mild-to-moderate hypothermia immediately after hypoxia-ischemic injury may be most effective following relatively mild insults. Protection appears to be lost if brief hypothermia is delayed by as little as 15 to 45 minutes after the primary insult. A more recent approach has been to try to suppress the secondary encephalopathic processes by maintaining hypothermia throughout the course of the secondary phase. An extended period of cooling (between 5 and 72 hours) appears to be more consistently effective and remains effective after signicant delays (possibly up to 6 hours) between the primary insult and the start of cooling, although the degree of neuroprotection progressively declines if cooling is initiated more than a few hours postinsult. (29) Potential adverse effects of induced hypothermia (the risk increasing with the depth of hypothermia) include increased blood viscosity, mild metabolic acidosis, decreased oxygen availability, intracellular shift of potassium, cardiac arrhythmias, coagulation abnormalities and platelet dysfunction, and choreic syndrome. (30) Hypothermia is in the process of translating from the clinical research experience to direct clinical applicae314 NeoReviews Vol.11 No.6 June 2010

tion. (31)(32) Clinical trials with hypothermia show some promising results but also have raised many questions that still need to be answered. (For further discussion on hypothermia for neonatal hypoxicischemic encephalopathy, see Shankaran S. Neonatal encephalopathy: treatment with hypothermia. NeoReviews. 2010;11:e85 e92.)

5. Benichou J, Zupan V, Fernandez H, et

al. Tocolytic magnesium sulphate and pediatric mortality. Lancet. 1997;351:290 291 6. Rouse D, Hirtz DG, Thom E, et al. A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med. 2008;359:895905 7. Moriette G, Barrat J, Truffert P, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very preterm newborn (of less than 33 weeks) with two-year neurological outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil. 2008;36:278 288 8. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009;1: CD004661 9. Palmer C, Vanucci RC, Towghi J. Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Pediatr Res. 1990; 27:332336 10. Williams GD, Palmer C, Heitjan DF, et al. Allopurinol preserves cerebral energy metabolism during perinatal hypoxic-ischemia: a 31P NMR study in anaesthetized immature rats. Neurosci Lett. 1992;144: 104 106 11. Palmer C, Roberts RL. Reduction of perinatal brain damage with oxypurinol treatment after hypoxic-ischemic injury. Pediatr Res. 1991;29:362A 12. Marro PJ, McGowan JE, Razdan B, et al. Effect of allopurinol on uric acid levels and brain cell membrane Na, K-ATPase activity during hypoxia in newborn piglets. Brain Res. 1994;650:9 15 13. Marro PJ, Hoffman D, Schneiderman R, et al. Effect of allopurinol on NMDA receptor modication following recurrent asphyxia in newborn piglets. Brain Res. 1998;787:7177 14. Russell GA, Cooke RW. Randomized controlled trial of allopurinol prophylaxis in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 1995;73:F27F31 15. Van Bel F, Shadid M, Moison RM, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;101:185193 16. Clancy RR, McGaurn SA, Goin JE, et al. Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics. 2001;108:6170 17. Bender MJ, Bos AF, Rademaker CM, et al. Early postnatal allopurinol does not improve short term outcome after severe

Erythropoietin
Yet another approach to neuroprotection has emerged recently in the form of erythropoietin. This glycoprotein possibly may be used as an adjunct to hypothermia. A review of the evidence of its possible efcacy to date is provided in Juul S. Erythropoietin as a neonatal neuroprotective agent. NeoReviews. 2010;11:e78 e84.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the clinical features, diagnosis, and management of perinatal hypoxicischemic encephalopathy. Know the management of perinatal asphyxia, including neural protective strategies.

References
1. Levene MI, Evans DJ, Mason S, et al. An
international network for evaluation of neuroprotective therapy after severe birth asphyxia. Semin Perinatol. 1999;23:226 233 2. Nelson KB, Grether JK. Can magnesium sulphate reduce the risk of cerebral palsy in very low birth weight infants? Pediatrics. 1995;95:263269 3. The Eclampsia Trial Collaborative Group. Which anticonvulsant for eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:14551463 4. Mittendorf R, Covert R, Boman J, et al. Is tocolytic magnesium sulphate associated with increased total pediatric mortality? Lancet. 1997;350:15171519

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birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91:F163F165 18. Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxicischemic encephalopathy. Cochrane Database Syst Rev. 2008;2:CD006817 19. Lee J, Kim MS, Park C, et al. Morphine prevents glutamate-induced death of primary rat neonatal astrocytes through modulation of intracellular redox. Immunopharmacol Immunotoxicol. 2004;26:1728 20. Yamakura T, Sakimura K, Shimoji K. Direct inhibition of the N-methyl-Daspartate receptor channel by high concentration of opioids. Anesthesiology. 1999;91: 10531063 21. Zhang J, Gibney GT, Zhao P. Neuroprotective role of delta-opioid receptors in cortical neurons. Am J Physiol. 2002;282: C1225C1234 22. Zhang J Haddad GG, Xia Y. Delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons

from glutamate-induced excitotoxic injury. Brain Res. 2000;8856:143153 23. Lim YJ, Zheng S, Zuo Z. Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemiareperfusion conditions. Anesthesiology. 2004; 100:562568 24. Mayeld KP, DAlecy LG. Role of endogenous opioid peptides in the acute adaptation to hypoxia. Brain Res. 1992;582: 226 231 25. Mayeld KP, DAlecy LG. Delta-1 opioid agonist acutely increases hypoxic tolerance. J Pharmacol Exp Ther. 1994;268: 683 688 26. Chein S, Oeltgen PR, Diana JN, et al. Extension of tissue survival time in multiorgan block preparation with a delta DADLE ([D-Ala2, D-leu5]-enkephalin). J Thorac Cardiovasc Surg. 1994;107:964 967 27. Angeles DM, Wycliffe N, Michelson D, et al. Use of opioids in asphyxiated term neonates: effects of neuroimaging and clinical outcome. Pediatr Res. 2005;57:873 878

28. Angeles DM, Ashwal S, Wycliffe ND,

et al. Relationship between opioid therapy, tissue damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonatales. Pediatr Res. 2007;60:614 621 29. Gunn AJ, Gunn TR. The pharmacology of neuronal rescue with cerebral hypothermia. Early Hum Dev. 1998;53:19 35 30. Wagner CL, Eicher DJ, Katikkaneni LD, et al. The use of hypothermia: a role in the treatment of neonatal asphyxia? Pediatr Neurol. 1999;21:429 443 31. Zanelli SA, Naylor M, Dobbins N, et al. Implementation of a hypothermia for HIE program: 2-year experience in a single NICU. J Perinatol. 2008;28:171175 32. Kapetanakis A, Azzopardi D, Wyatt J, et al. Therapeutic hypothermia for neonatal encephalopathy: a UK survey of opinion, practice and neuron-investigation at the end of 2007. Acta Paediatr. 2009;98: 631 635

NeoReviews Quiz
8. Several neuroprotective approaches have been proposed for the treatment of hypoxic-ischemic encephalopathy in the newborn. These treatments have been examined in laboratory animals for feasibility and evaluated in small and large randomized trials in human neonates for safety and efcacy. Of the following, the most promising neuroprotective treatment in the process of translation from research to clinical application is: A. B. C. D. E. Allopurinol. Erythropoietin. Hypothermia. Magnesium sulfate. Opioids.

9. A term newborn is delivered by emergent cesarean section for fetal distress from spontaneous placental abruption. The infants Apgar scores are 1, 3, and 5 at 1, 5, and 10 minutes after birth, respectively. The umbilical cord blood pH is 6.82, and base decit is 24 mEq/L. After initial stabilization, the infant is admitted to the neonatal intensive care unit for administration of hypothermia. Of the following, the factor most critical for the neuroprotective benets of hypothermia in this infant is: A. B. C. D. E. Depth of cooling. Duration of cooling. Technical method of cooling. Timing of initiation of cooling. Whole body versus selective head cooling.
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Pharmacology Review : Neuroprotective Treatments for Hypoxic-Ischemic Injury Peter J. Marro and Maria Delivoria-Papadopoulos Neoreviews 2010;11;e311 DOI: 10.1542/neo.11-6-e311

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/11/6/e311 This article cites 32 articles, 7 of which you can access for free at: http://neoreviews.aappublications.org/content/11/6/e311#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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